Oxadiazolopyridine derivatives for use as ghrelin O-acyl transferase (GOAT) inhibitors

ABSTRACT

The present invention relates to compounds of general formula I,wherein the groups R1, R2 and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to ghrelin O-acyl transferase (GOAT) and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular obesity.

FIELD OF THE INVENTION

The present invention relates to novel oxadiazolopyridine derivatives,that are inihibitors of the ghrelin O-acyl transferase (GOAT), toprocesses for their preparation, to pharmaceutical compositionscontaining these compounds and to their medical use for the prophylaxisand/or treatment of diseases which can be influenced by the modulationof the function of the ghrelin O-acyl transferase (GOAT). Particularly,the pharmaceutical compositions of the invention are suitable for theprophylaxis and/or therapy of metabolic diseases, such as obesity,including, but not limited to obesity in patients suffering fromPrader-Willi-Syndrome (PWS), insulin resistance and diabetes,particularly type 2 diabetes.

BACKGROUND OF THE INVENTION

Ghrelin O-Acyltransferase (GOAT) is a member of the membrane-boundO-acyl transferase (MBOAT) protein family, and the only enzyme in humanscapable of promoting an acylation reaction on the peptide hormoneghrelin. By linking a medium-chain fatty acid to the Serine-3 positionof the 28-amino acid peptide, GOAT converts unacylated ghrelin (UAG) toacylated ghrelin (AG) which is the natural ligand of the ghrelinreceptor GHSR1a (growth hormone secretagogue receptor 1a). The ghrelinreceptor is expressed in various areas of the brain involved in energyhomeostasis. Activation of the receptor by AG results in stimulation ofneuronal pathways leading to increased food intake, fat deposition andweight gain thus linking the ghrelin system to obesity. In humans, AG inplasma peaks immediately before mealtimes and drops in response to foodintake (D. E. Cummings et al., Diabetes (2001) 50(8), 1714-1719).Infusion of AG has been shown to increase food intake in lean and obesesubjects (M. R. Druce et al., Int. J. Obes. (2005), 29(9), 1130-1136).So far no receptor has been identified for UAG, but it has been shown tohave functional antagonistic effects to AG at least with respect to itsmetabolic properties (W. Zhang et al., Endocrinology (2008) 149 (9),4710-4716). Since an inhibitor of GOAT would substantially diminish thelevel of the GHSR1a ligand AG and concomitantly increase the functionalantagonist UAG, it would be useful for the treatment of obesity as anadjunct to a reduced-calorie diet and increased physical activity forchronic weight management.

Insatiable hunger and severe obesity are characteristic features of thePrader-Willi-Syndrome (PWS), a genetically caused orphan disease with acomplex pathology. AG levels in plasma of PWS subjects are elevated andAG/UAG ratios are increased suggesting a causal relationship (N. Wierupet al., Regulatory Peptides (2002) 107, 63-69; R. J. Kuppens et al.,Endocrine (2015) 50(3), 633-642). Therefore GOAT inhibitors may beeffective in reducing food craving behavior and body weight in PWSpatients ameliorating one major burden affecting the patients and theirfamilies.

Furthermore the ghrelin system seems to play a major role in glucosehomeostasis. Administration of AG to human subjects leads to suppressionof glucose-induced insulin secretion and an increase in plasma glucose.Infusion of UAG is able to counteract the hyperglycemic effect of AG (F.Broglio et al., J. Clin. Endocrinol. Metab. (2004) 89, 3062-3065). Theexpression of GOAT, ghrelin and GHSR1a in human pancreatic isletssuggests a paracrine role on insulin secretion (A. DelParigi et al., J.Clin. Endocrinol. Metab. (2002) 87(12), 5461-5464). In addition UAGpromotes pancreatic β-cell and human islet cell survival in vitro (R.Granata et al., Endocrinology (2007) 148(2), 512-529) and preventsdiabetes in streptozotocin treated rats (R. Granata et al., J. Med.Chem. (2012) 55(6), 2585-2596). Thus treatment with a GOAT inhibitor isexpected to improve glucose homeostasis in patients with type 2 diabetesor obese with impaired glucose tolerance.

OBJECT OF THE PRESENT INVENTION

The object of the present invention is to provide new compounds,hereinafter described as compounds of formula I, in particular newoxadiazolopyridine derivatives, which are active with regard to theghrelin O-acyl transferase (GOAT), notably they are ghrelin O-acyltransferase (GOAT) inhibitors.

A further object of the present invention is to provide new compounds,in particular oxadiazolopyridine derivatives, which have an inhibitingeffect on ghrelin O-acyl transferase (GOAT) in vitro and/or in vivo andpossess suitable pharmacological and pharmacokinetic properties to usethem as medicaments.

A further object of the present invention is to provide effectiveghrelin O-acyl transferase (GOAT) inhibitors, in particular for thetreatment of metabolic disorders, for obesity, including, but notlimited to obesity in patients suffering from Prader-Willi-Syndrome(PWS), insulin resistance and diabetes, in particular type 2 diabetesmellitus.

A further object of the present invention is to provide methods fortreating a disease or condition mediated by the inhibition of ghrelinO-acyl transferase (GOAT) in a patient.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further object of the present invention is to provide a combination ofat least one compound according to the invention with one or moreadditional therapeutic agents.

Further objects of the present invention become apparent to the oneskilled in the art by the description hereinbefore and in the followingand by the examples.

Ghrelin O-acyl transferase (GOAT) inhibitors are known in the art, seefor example the compounds disclosed in WO 2013/125732 and WO2015/073281. The oxadiazolopyridine derivatives of the present inventionare structurally quite different and may provide several advantages,such as enhanced potency, high metabolic and/or chemical stability, highselectivity and tolerability, enhanced solubility, the ability to crossthe blood-brain barrier and the possibility to form stable salts.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to a compound of formula

wherein

-   X is CH or N;-   R¹ is selected from the group R¹-G1 consisting of CH₃, —CH₂OH and    Cl;-   R² is independently of each other selected from the group R²-G1    consisting of H, F, Cl, Br, I, CN, C₁₋₆-alkyl, C₃₋₇-cycloalkyl, OH,    —O—(C₁₋₆-alkyl), —O—(C₃₋₇-cycloalkyl),    —O—(C₁₋₃-alkyl)-(C₃₋₇-cycloalkyl), —O-heterocyclyl,    —O—(C₁₋₃-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl,    —S—(C₁₋₃-alkyl), —SO—(C₁₋₃-alkyl), —SO₂—(C₁₋₃-alkyl), —NH₂,    —NH—(C₁₋₆-alkyl), —NH—(C₃₋₆-cycloalkyl),    —NH—(C₁₋₃-alkyl)-heterocyclyl, —NH—(C₁₋₆-alkyl)-C(═O)—NH₂,    —C(═O)—NH₂, —C(═O)—NH—(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂, —C(═O)OH,    —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₄-alkyl),    —C₁₋₃-alkyl-C(═O)—O—(C₁₋₄-alkyl), heterocyclyl, heteroaryl and    5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,    -   wherein each alkyl or cycloalkyl group is optionally        independently substituted with one or more substituents selected        from the group consisting of F, CN and OH, and    -   wherein each heterocyclyl group is selected from the group        consisting of mono- or spirocyclic 4-7-membered cycloalkyl        group, in which 1, 2 or 3 CH₂-groups are independently of each        other replaced by O, S, NH or C=O, and    -   wherein each heterocyclyl group is optionally substituted with 1        or 2 substituents independently of each other selected from F,        OH and C₁₋₃-alkyl,    -   wherein each aryl group is selected from a group consisting of        phenyl and naphthyl, and    -   wherein each heteroaryl group is selected from a 5-membered        aromatic cycle containing 1 or 2 heteroatoms independently        selected from N, O and S or from a 6-membered aromatic cycle        containing 1 or 2 N, and    -   wherein each aryl or heteroaryl group is optionally substituted        with 1 or 2 substituents independently selected from a group        consisting of F, CN and C₁₋₃-alkyl, which is optionally        substituted with one or more F;

or, if two groups R² are attached to adjacent C atoms of the pyridine orpyrimidine group, they may be linked with each other and together form a—O—CH₂—O—, —O—CH₂—CH₂—O— or —O—CH₂—CH₂—CH₂—O— bridge, in which 1 or 2Hatoms may be replaced with F or C₁₋₃-alkyl; and

n is 1, 2 or 3;

wherein each of the above-mentioned alkyl groups may be substituted withone or more F;

the isoforms, tautomers, stereoisomers, metabolites, prodrugs, solvates,hydrates, and the salts thereof, particularly the physiologicallyacceptable salts thereof with inorganic or organic acids or bases, orthe combinations thereof.

The extension -Gn used within the definitions is meant to identify genusn of the respective substituent. For example, R-G1 defines genus 1 ofthe substituent R.

The expression “optionally substituted with 1 or more F atoms” meansthat none or one up to successively all H atoms bound to carbon atoms ofthe respective group or submoiety may be replaced by F atoms, preferably1 to 5H atoms or, more preferred, 1 to 3H atoms may be replaced by Fatoms.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by inhibiting ghrelin O-acyltransferase (GOAT) in a patient in need thereof characterized in that acompound of general formula I or a pharmaceutically acceptable saltthereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder, such as obesity,including, but not limited to obesity in patients suffering fromPrader-Willi-Syndrome, insulin resistance and diabetes, in particulartype 2 diabetes mellitus, in a patient in need thereof characterized inthat a therapeutically effective amount of a compound of general formulaI or a pharmaceutically acceptable salt thereof is administered to thepatient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the inhibition of ghrelin O-acyltransferase (GOAT) in a patient that includes the step of administeringto the patient in need of such treatment a therapeutically effectiveamount of a compound of the general formula I or a pharmaceuticallyacceptable salt thereof in combination with a therapeutically effectiveamount of one or more additional therapeutic agents.

In a further aspect this invention relates to the use of a compound ofthe general formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are mediated by the inhibitionof ghrelin O-acyl transferase (GOAT).

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly X, R¹, R² and n are defined as above and hereinafter. Ifresidues, substituents, or groups occur several times in a compound,they may have the same or different meanings. Some preferred meanings ofindividual groups and substituents of the compounds according to theinvention will be given hereinafter. Any and each of these definitionsmay be combined with each other.

X:

X is preferably CH or N.

According to one embodiment, X is CH.

According to another embodiment, X is N.

R¹:

R¹-G1:

The group R₁ is preferably selected from the group R¹-G1 as deinfedhereinbefore.

R¹-G2:

In one embodiment the group R¹ is selected from the group R¹-G2consisting of CH₃ and Cl.

R¹-G3:

In another embodiment the group R¹ is selected from the group R¹-G3consisting of CH₃ and —CH₂OH.

R¹-G4:

In another embodiment the group R¹ is selected from the group R¹-G4consisting of —CH₂OH and Cl.

R¹-G5:

In another embodiment the group R¹ is selected from the group R¹-G5consisting of CH₃.

R¹-G6:

In another embodiment the group R¹ is selected from the group R¹-G6consisting of —CH₂OH.

R¹-G7:

In another embodiment the group R¹ is selected from the group R¹-G7consisting of Cl.

R²:

R²-G1:

The group R² is preferably selected from the group R²-G1 as definedhereinbefore.

R²-G2:

In another embodiment the group R² is independently of each otherselected from the group R²-G2 consisting of H, F, Cl, Br, CN,C₁₋₆-alkyl, C₃₋₇-cycloalkyl, OH, —O—(C₁₋₆-alkyl),—O—(C₁₋₃-alkyl)-(C₃₋₇-cycloalkyl), —O-heterocyclyl,—O—(C₁₋₃-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C₁₋₃-alkyl),—SO₂—(C₁₋₃-alkyl), —NH₂, —NH—(C₁₋₆-alkyl), —NH—(C₃₋₆-cycloalkyl),—NH—(C₁₋₃-alkyl)-heterocyclyl, —NH—(C₁₋₆-alkyl)-C(═O)—NH₂, —C(═O)—NH₂,—C(═O)—NH—(C₁₋₃-alkyl), —C(═O)—(C₁₋₄-alkyl),—C₁₋₃-alkyl-C(═O)—O—(C₁₋₄-alkyl), heterocyclyl, heteroaryl and5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl orcycloalkyl group is optionally independently substituted with one ormore substituents selected from the group consisting of F, CN and OH,and

-   -   wherein each heterocyclyl group is selected from a mono- or        spirocyclic 4-7-membered cycloalkyl group, in which 1, 2 or 3        CH₂-groups are independently of each other replaced by O, S, NH        or C═O, and    -   wherein each heterocyclyl group is optionally substituted with 1        or 2 substituents independently of each other selected from F,        OH and C₁₋₃-alkyl,    -   wherein each aryl group is selected from a group consisting of        phenyl and naphthyl, and    -   wherein each heteroaryl group is selected from a 5-membered        aromatic cycle containing 1 or 2 heteroatoms independently        selected from N, O and S or from a 6-membered aromatic cycle        containing 1 or 2 N, and    -   wherein each aryl or heteroaryl group is optionally substituted        with 1 or 2 substituents independently selected from a group        consisting of F and C₁₋₃-alkyl, which is optionally substituted        with one or more F;

or, if two groups R² are attached to adjacent C atoms of the pyridine orpyrimidine group, they may be linked with each other and together form a—O—CH₂—O—, —O—CH₂—CH₂—O— or —O—CH₂—CH₂—CH₂—O— bridge.

R²-G3:

In another embodiment the group R² is independently of each otherselected from the group R²-G3 consisting of F, Cl, Br, CN, C₁₋₃-alkyl,C₃₋₆-cycloalkyl, —O—(C₁₋₄-alkyl), —O—CH₂-cyclopropyl,—O—CH₂-heterocyclyl, —O-phenyl, —O-heteroaryl, —S—CH₃, —NH₂,—NH—(C₁₋₄-alkyl), —NH—(C₃₋₅-cycloalkyl), —NH—(CH₂-heterocyclyl),—NH—(C₁₋₄-alkyl)-C(═O)—NH₂, —C(═O)—NH—(C₁₋₃-alkyl), —C(═O)—(C₁₋₄-alkyl),heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,

-   -   wherein each alkyl or cycloalkyl group is optionally        independently substituted with one to three F atoms or with one        CN or one OH, and    -   wherein each heterocyclyl group is selected from a group        consisting of oxetanyl, tetrahydrofuranyl, azetidinyl,        pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and    -   wherein each heterocyclyl group is optionally substituted with 1        or 2 substituents independently of each other selected from F,        OH and CH₃,    -   wherein each heteroaryl group is selected from a group        consisting of furanyl, isoxazolyl, thiazolyl and pyrazolyl, and    -   wherein each heteroaryl group is optionally substituted with 1        or 2 substituents independently selected from a group consisting        of F, CH₃ and CF₃.

R²-G4:

In another embodiment the group R² is independently of each otherselected from the group R²-G4 consisting of F, Cl, Br, CN, CH₃,C₃₋₅-cycloalkyl, —O—(C₁₋₄-alkyl), —O—CH₂-heterocyclyl, —O-phenyl,—S—CH₃, —NH₂, —NH—(C₁₋₄-alkyl), —NH—(C₃₋₅-cycloalkyl),—NH—(CH₂-heterocyclyl), —NH—(C₁₋₄-alkyl)-C(═O)—NH₂, heterocyclyl,heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,

-   -   wherein each alkyl or cycloalkyl group is optionally        independently substituted with one to three F atoms or with one        CN or one OH, and    -   wherein each heterocyclyl group is selected from a group        consisting of oxetanyl, azetidinyl, pyrrolidinyl, morpholinyl        and 1,4-diazepan-5-one, and    -   wherein each heterocyclyl group is optionally substituted with 1        or 2 substituents independently selected from F, OH and CH₃, and    -   wherein each heteroaryl group is selected from a group        consisting of furanyl and thiazolyl.

R²-G5:

In another embodiment the group R² is independently selected from thegroup R²-G5 consisting of:

F, Cl, Br, —CN, —CF₃,

—O —CH₃, —O—CHF₂, —O—CH₂—CH₂—F, —O—CH₂—CHF₂, —O—CH₂—CF₃,—O—CH₂—CH₂—CH₂—F, —O—CH₂—CF₂—CH₃,

—S—CH₃, —NH₂, —NH—CH₂—CH₂—CH₂—F, —NH—CH₂—CH₂—CHF₂,

R²-G6:

In another embodiment the group R² is independently selected from thegroup R²-G6 consisting of H, F, Cl, Br, CN, —CF₃, —CHF₂, —CH₂F, —O—CF₃,—O—CHF₂, —O—CH₂F, —O—CH₃, —NH₂, —CO—NH₂, —CO₂H.

n

The index n is an integer selected from 1, 2 and 3.

Preferably, n is 2 or 3.

In another embodiment, n is 1 or 2.

More preferably, n is 2.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1 to I.11, wherein any tautomers,solvates, hydrates and salts thereof, in particular the pharmaceuticallyacceptable salts thereof, are encompassed. R^(2a) and R^(2b) are asdefined for R².

Examples of preferred subgeneric embodiments (E) according to thepresent invention are set forth in the following table 1, wherein eachsubstituent group of each embodiment is defined according to thedefinitions set forth hereinbefore and wherein all other substituents ofthe formulae I, I.1, I.2, I.3, I.4, I.5, I.6, I.7, I.8, I.9, I.10 andI.11 are defined according to the definitions set forth hereinbefore.For example, the entry -G1 in the column under R— and in the line of E1means that in embodiment E1 substituent R is selected from thedefinition designated R-G1. The same applies analogously to the othervariables incorporated in the general formulae.

TABLE 1 E formula X R¹— R²— n E1 I CH or N —G1 —G1 1, 2 or 3 E2 I CH orN —G1 —G2 1, 2 or 3 E3 I CH or N —G5 —G2 1, 2 or 3 E4 I CH or N —G5 —G31, 2 or 3 E5 I CH or N —G5 —G4 1, 2 or 3 E6 I CH or N —G5 —G5 1, 2 or 3E7 I CH or N —G5 —G6 1, 2 or 3 E8 I CH or N —G5 —G1 1 or 2 E9 I CH or N—G5 —G2 1 or 2 E10 I CH or N —G5 —G3 1 or 2 E11 I CH or N —G5 —G4 1 or 2E12 I CH or N —G5 —G5 1 or 2 E13 I CH or N —G5 —G6 1, 2 or 3 E14 I CH orN —G5 —G1 1 E15 I CH or N —G5 —G2 1 E16 I CH or N —G5 —G3 1 E17 I CH orN —G5 —G4 1 E18 I CH or N —G5 —G5 1 E19 I CH or N —G5 —G6 1 E20 I CH orN —G5 —G1 2 E21 I CH or N —G5 —G2 2 E22 I CH or N —G5 —G3 2 E23 I CH orN —G5 —G4 2 E24 I CH or N —G5 —G5 2 E25 I CH or N —G1 —G6 2 E26 I CH —G1—G1 1, 2 or 3 E27 I CH —G1 —G2 1, 2 or 3 E28 I CH —G1 —G3 1, 2 or 3 E29I CH —G1 —G4 1, 2 or 3 E30 I CH —G1 —G5 1, 2 or 3 E31 I CH —G1 —G6 1, 2or 3 E32 I CH —G5 —G1 1 or 2 E33 I CH —G5 —G2 1 or 2 E34 I CH —G5 —G3 1or 2 E35 I CH —G5 —G4 1 or 2 E36 I CH —G5 —G5 1 or 2 E37 I CH —G5 —G6 1or 2 E38 I CH —G5 —G1 1 E39 I CH —G5 —G2 1 E40 I CH —G5 —G3 1 E41 I CH—G5 —G4 1 E42 I CH —G5 —G5 1 E43 I CH —G5 —G6 1 E44 I CH —G5 —G1 2 E45 ICH —G5 —G2 2 E46 I CH —G5 —G3 2 E47 I CH —G5 —G4 2 E48 I CH —G5 —G5 2E49 I CH —G5 —G6 2 E50 I N —G1 —G1 1, 2 or 3 E51 I N —G1 —G2 1, 2 or 3E52 I N —G1 —G3 1, 2 or 3 E53 I N —G1 —G4 1, 2 or 3 E54 I N —G1 —G5 1, 2or 3 E55 I N —G1 —G6 1, 2 or 3 E56 I N —G5 —G1 1 or 2 E57 I N —G5 —G2 1or 2 E58 I N —G5 —G3 1 or 2 E59 I N —G5 —G4 1 or 2 E60 I N —G5 —G5 1 or2 E61 I N —G6 —G6 1 or 2 E62 I N —G1 —G1 1 E63 I N —G1 —G2 1 E64 I N —G1—G3 1 E65 I N —G1 —G4 1 E66 I N —G1 —G5 1 E67 I N —G1 —G6 1 E68 I N —G5—G1 1 E69 I N —G5 —G2 1 E70 I N —G5 —G3 1 E71 I N —G5 —G4 1 E72 I N —G5—G5 1 E73 I N —G1 —G6 1 E74 I N —G1 —G1 2 E75 I N —G1 —G2 2 E76 I N —G1—G3 2 E78 I N —G1 —G4 2 E79 I N —G1 —G5 2 E80 I N —G1 —G6 2 E81 I N —G5—G1 2 E82 I N —G5 —G2 2 E83 I N —G5 —G3 2 E84 I N —G5 —G4 2 ESS I N —G5—G5 2 E86 I N —G5 —G6 2 E87 I.2 — —G5 —G1 — E88 I.2 — —G5 —G2 — E89 I.2— —G5 —G3 — E90 I.2 — —G5 —G4 — E91 I.2 — —G5 —G5 — E92 I.2 — —G5 —G6 —E93 I.3 — —G5 —G1 — E94 I.3 — —G5 —G2 — E95 I.3 — —G5 —G3 — E96 I.3 ——G5 —G4 — E97 I.3 — —G5 —G5 — E98 I.3 — —G5 —G6 —

Another embodiment concerns those compounds of formula

wherein

R¹ is CH₃;

R^(2a) and R^(2b) are each independently selected from the groupconsisting of:

F, Cl, Br, —CN, —CF₃,

—O—CH₃, —O—CHF₂, —O—CH₂—CH₂—F, —O—CH₂—CHF₂, —O—CH₂—CF₃,—O—CH₂—CH₂—CH₂—F, —O—CH₂—CF₂—CH₃,

—S—CH₃, —NH₂, —NH—CH₂—CH₂—CH₂—F, —NH—CH₂—CH₂—CHF₂,

and

n is 1 or 2;

or a salt thereof, particularly a pharmaceutically acceptable saltthereof.

Preferred compounds of the invention include:

or a salt thereof, particularly a pharmaceutically acceptable saltthereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis forexample.

Moreover, the invention provides processes for making a compound ofFormula I.

Optimal reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC) or LC-MS, ifdesired, and intermediates and products may be purified bychromatography on silica gel, HPLC and/or by recrystallization. Theexamples which follow are illustrative and, as recognized by one skilledin the art, particular reagents or conditions could be modified asneeded for individual compounds without undue experimentation. Startingmaterials and intermediates used, in the methods below, are eithercommercially available or easily prepared from commercially availablematerials by those skilled in the art.

A compound of Formula I may be made by the method outlined in Scheme 1,2, or 3:

As illustrated in Scheme 1 reacting of the acetylacetone with analkylating agent of Formula II (Y═Cl, Br, I, OMs, OTs) in the presenceof a suitable base such as potassium, sodium or caesium carbonate, in asuitable solvent such as methanol or ethanol, provides a compound ofFormula III.

Reacting of the compound of Formula III with the4-amino-1,2,5-oxadiazole-3-carbonitrile (Chemistry of HeterocyclicCompounds (New York, N.Y., United States), 1994, vol. 30, #5 p. 608-611)in the presence of a suitable Lewis acid such as tin (IV) chloride, in asuitable solvent such as toluene or benzene, provides a compound ofFormula I.

As illustrated in Scheme 2 reacting of the ethyl acetoacetate with the4-amino-1,2,5-oxadiazole-3-carbonitrile (Chemistry of HeterocyclicCompounds (New York, N.Y., United States), 1994, vol. 30, #5 p. 608-611)in the presence of a suitable Lewis acid such as tin (IV) chloride, in asuitable solvent such as toluene or benzene, provides ester IV.

Reduction of the esther IV with the reducing agent such as sodiumbis(2-methoxyethoxy)aluminiumhydride (Red-Al®) or lithium aluminiumhydride, in a suitable solvent such as toluene/tetrahydrofuran mixture,provides alcohol V. Alcohol V can be converted into the correspondingderivatives VI using suitable reagents and solvents, such as:thionylchloride in dimethylformamide (to prepare VIa); phosphorustribromide in dichloromethane (to prepare VIb); glacial acetic acid (toprepare VIc).

Iodide of formula VII can be converted into the correspondinghetarylmagnesium chloride of formula VIII using suitable reagent such asisopropylmagnesium chloride lithium chloride complex, in a suitablesolvent such as tetrahydrofuran. Reacting of hetarylmagnesium chlorideof formula VIII with the compound of formula VI in the presence ofcopper(I)cyanide di(lithium chloride) complex, in a suitable solventsuch as tetrahydrofuran, provides a compound of formula I.

As illustrated in Scheme 3 saponification of the ester of formula IV,using a suitable reagent such as lithium, sodium or potassium hydroxide,in a suitable solvent such as tetrahydrofuran, methanol or ethanol,provides an acid of formula IX. Reacting of the acid of formula IX withN-iodosuccinimide, in the presence of a suitable base such as sodiumhydrogen carbonate, in a suitable solvent such as N,N-dimethylformamideor acetonitrile, provides a compound of formula X. The protection anddeprotection of functional groups is described in ‘Protective Groups inOrganic Synthesis’, T. W. Greene and P. G. M. Wuts, Wiley-Interscience.For example, for the protection of an amine of Formula X,N,N-dimethylformamide dimethyl acetal may be used in a suitable solventsuch as N,N-dimethylformamide to provide a compound of Formula XI.

Zincation of a compound of formula XI may be carried out in situ using asuitable reagent such as diisopropylzinc, in the presence of lithiumacetylacetonate, in a suitable solvent such as N-methyl-2-pyrrolidone.These can be coupled in a (transition) metal catalyzed reaction with acompound of formula II (Y═Br, I) using a suitable catalyst such as[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), in asuitable solvent such as N-methyl-2-pyrrolidone to provide a compound offormula XII. Deprotection a compound of formula XII with concentratedaqueous hydrochloric acid, in a suitable solvent such as methanol orethanol, provides a compound of formula I.

Further modifications of compounds of formula I by methods known in theart and illustrated in the Examples below, may be used to prepareadditional compounds of the invention.

The synthetic routes presented may rely on the use of protecting groups.For example, potentially reactive groups present, such as hydroxy,carbonyl, carboxy, amino, alkylamino, or imino, may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction. Suitable protecting groups for the respectivefunctionalities and their removal are well known to the one skilled inthe art and are described in the literature of organic synthesis forexample in “Protecting Groups, 3^(rd) Edition”, Philip J. Kocienski,Theime, 2005 or “Greene's Protective Groups in Organic Synthesis, 4thEdition”, Peter G. M. Wuts, Theadora W. Greene, John Wiley and Sons,2007.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers as mentioned below. Thus, for example,cis/trans mixtures may be resolved into their cis and trans isomers andracemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se intotheir optical antipodes and diastereomeric mixtures of compounds ofgeneral formula I may be resolved into their diastereomers by takingadvantage of their different physico-chemical properties using methodsknown per se, e.g. chromatography and/or fractional crystallization; ifthe compounds obtained thereafter are racemates, they may be resolvedinto the enantiomers as mentioned below.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallization from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound. Saltsmay be formed with enantiomerically pure acids for basic compounds andwith enantiomerically pure bases for acidic compounds. Diastereomericderivatives are formed with enantiomerically pure auxiliary compounds,e.g. acids, their activated derivatives, or alcohols. Separation of thediastereomeric mixture of salts or derivatives thus obtained may beachieved by taking advantage of their different physicochemicalproperties, e.g. differences in solubility; the free antipodes may bereleased from the pure diastereomeric salts or derivatives by the actionof suitable agents. Optically active acids commonly used for such apurpose as well as optically active alcohols applicable as auxiliaryresidues are known to those skilled in the art.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the pharmaceuticallyacceptable salts. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike.

For example, such salts include salts from benzenesulfonic acid, benzoicacid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid,hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonicacid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonicacid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid andtartaric acid.

Further pharmaceutically acceptable salts can be formed with cationsfrom ammonia, L-arginine, calcium, 2,2′-iminobisethanol, L-lysine,magnesium, N-methyl-D-glucamine, potassium, sodium andtris(hydroxymethyl)-aminomethane.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embrace both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refer to the inhibition of the ghrelinO-acyl transferase (GOAT) with one or more compounds of the presentinvention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refer to the (i) treatment, including prevention ofthe particular disease or condition, (ii) attenuation, amelioration, orelimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

Determination of hGOAT Activity in HEK293 Cells after Incubation withTest Compound

Principle:

HEK293 cells stably transfected with two expression vectors, one codingfor preproghrelin cDNA and a second for the expression of human GOATcDNAare used as a cellular model. After feeding the cells with octanoic acidfor 5 hours, acyl-ghrelin is measured in cell culture medium by an ELISAprocedure.

Materials:

Cellline: Hek293 hGOAT/PPGhrl Clone #1B8Sodium octanoate, Sigma,Cat.-No. C5038

BSA: Sigma, Cat.-No. A8806

BD Poly-D-Lysin 384-well Plates, black-clear polystyrene BD BioscienceCat.-No. 356697348-well ELISA human acylated Ghrelin Kit purchased fromBertin Pharman (detailed composition of buffers e.g. wash-puffer, ELISAbuffer not known)

All further reagents used were of highest analytical grade available.

Method:

Cells are plated with a density of 5000 cells/well in 384-wellpoly-D-lysin plates and incubated for 1 day at 37° C., 5% CO2 in DMEMmedium, 10% FCS, 1×NEAA, Puromycin (0.5 μg/ml) and G418 (1 mg/ml). Thenthe medium is changed to a identical medium without FCS and containingOctanoate-BSA (final concentration 100 μM each) and compound in DMSO(final DMSO concentration 0.3%). After incubation for 5 hoursacylghrelin in the medium is measured by ELISA

The medium sample is diluted 1:25 in Elisa buffer, A 25 ul aliquot istransferred to a 384-well ELISA plate previously washed 4 times with 100μL wash buffer, and 25 μl tracer-solution is added. After incubationovernight (˜20 h) at 4° C. temperature the plate is washed 4 times with100 μl wash-buffer per well. Finally 50 μl Ellman's reagent is added toeach well and the plate is incubated in the dark for 20 minutes. Theabsorbance is measured at 405 nm in an Envision multilabel reader andthe amount of acylated ghrelin is calculated according to a acylatedghrelin standard curve provided in the same plate.

Each assay plate contains wells with vehicle controls (1% DMSO) for themeasurement of non-inhibited transfer reaction (=100% Ctl) and wellswith 10 μM ([Dap3]-Ghrelin) as controls for fully inhibited GOAT enzyme

The analysis of the data is performed by calculation of the percentageof acyl-ghrelin produced in the presence of test compound compared tothe amount of acyl-ghrelin produced in the vehicle control samples. Aninhibitor of the GOAT enzyme will give values between 100% CTL (noinhibition) and 0% CTL (complete inhibition). IC50 values are calculatedwith Assay Explorer or other suited software based on curve fitting ofresults of 8 different compound concentrations.

Results:

IC50 example [nM] 1 1.4 2 3.6 3 0.46 4 1.7 5 0.24 6 0.61 7 0.95 8 0.42 90.44 10 13 11 0.13 12 6.5 13 4.4 14 0.67 15 0.038 16 0.28 17 0.22 180.32 19 0.047 20 0.17 21 0.03 22 0.066 23 0.082 24 0.12 25 4.4 26 8.8 271.7 28 48 29 16 30 2.7 31 1.8 32 0.44 33 0.3 34 3.2 35 1.8 36 6.9 37 0.238 2.6 39 0.18 40 5.2 41 1.2 42 0.073 43 0.37 44 0.17 45 1.2 46 0.22 472.4 48 0.18 49 0.15 50 2.5 51 20 52 0.48 53 2.6 54 0.24 55 3.9 56 0.7257 0.1 58 2.8 59 0.34 60 0.48 61 0.29 62 0.21 63 0.48 64 0.1 65 0.29 660.14 67 0.05 68 0.11 69 0.58 70 0.082 71 0.22 72 1.1 73 0.33 74 2.0 752.7 76 14 77 3.8 78 0.36 79 0.59 80 3.8 81 7.0 82 1.0 83 0.077 84 0.2185 6.9 86 19 87 9 88 3.3 89 0.43 90 0.54 91 0.35 92 0.058 93 0.32 940.058 95 0.082 96 0.079 97 0.022 98 1.9 99 0.072 100 0.034 101 0.074 1020.074 103 0.086 104 0.98 105 0.12 106 0.11 107 0.33 108 0.026 109 0.093110 0.28 111 0.1 112 0.22 113 31 114 3.9 115 1.2 116 0.83 117 0.19 1180.085 119 0.091 120 4.3 121 0.045 122 0.033 123 0.026 124 0.056 1250.038 126 0.17 127 0.1 128 0.096 129 0.052 130 0.02 131 0.097 132 0.1133 0.099 134 0.24 135 0.2 136 0.033 137 0.054 138 0.075 139 0.02 1400.15 141 0.14 142 0.027 143 0.046 144 0.055 145 0.32 146 1.1 147 0.25148 0.15 149 0.027 150 2.3 151 1.8 152 0.6 153 0.56 154 0.17 155 1.2 1563.5 157 0.26 158 1.7 159 15 160 3.0 161 0.89 162 4.6 163 2.5 164 7.4 16514 166 0.38 167 0.82 127 0.1

In view of their ability to modulate the activity of ghrelin O-acyltransferase (GOAT), in particular an inhibitory activity, the compoundsof general formula I according to the invention, including thecorresponding salts thereof, are suitable for the treatment of all thosediseases or conditions which may be affected or which are mediated bythe inhibition of ghrelin O-acyl transferase (GOAT).

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the inhibition of ghrelin O-acyl transferase(GOAT) in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the inhibition of ghrelinO-acyl transferase (GOAT) in a mammal that includes the step ofadministering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound or apharmaceutical composition of the present invention.

Diseases and conditions mediated by inhibitors of ghrelin O-acyltransferase (GOAT) embrace obesity, including, but not limited toobesity in patients suffering from Prader-Willi-Syndrome (PWS), bodyweight regain, diabetes, particularly type 2 diabetes mellitus, insulinresistance, hyperphagia in PWS, Binge eating disorder, nighttime eatingsyndrome and alcohol and/or narcotic dependence.

Preferably, the compounds of the invention are used for treatingobesity, body weight regain, type 2 diabetes, insulin resistance, andhyperphagia and obesity in PWS.

More preferably, the compounds of the invention are used for treatingobesity, body weight regain, type 2 diabetes and insulin resistance.

In particular, the compounds and pharmaceutical compositions accordingto the invention are suitable for the treatment of obesity, including,but not limited to obesity in patients suffering fromPrader-Willi-Syndrome, body weight regain, diabetes, in particular type2 diabetes mellitus, and insulin resistance.

The compounds according to the invention are most particularly suitablefor treating obesity.

The present invention further provides a GOAT inhibitor of the inventionfor use in a method of medical treatment.

GOAT inhibitors are useful, inter alia, in the reduction of food intake,promotion of weight loss, and inhibition or reduction of weight gain. Asa result, they may be used for treatment of a variety of conditions,diseases, or disorders in a subject, including, but not limited to,obesity and various obesity-related conditions, diseases, or disorders,such as diabetes (e.g. type 2 diabetes). It will be understood that theGOAT inhibitors may thus be administered to subjects affected byconditions characterised by inadequate control of appetite or otherwiseover-feeding, such as binge-eating disorder and Prader-Willi syndrome.

Thus, the invention provides a GOAT inhibitor of the invention for usein a method of treating, inhibiting or reducing weight gain, promotingweight loss and/or reducing excess body weight. Treatment may beachieved, for example, by control of appetite, feeding, food intake,calorie intake and/or energy expenditure.

The invention also provides a GOAT inhibitor of the invention for use ina method of treating obesity as well as associated diseases, disordersand health conditions, including, but not limited to, morbid obesity,obesity prior to surgery, obesity-linked inflammation, obesity-linkedgallbladder disease and obesity-induced sleep apnea and respiratoryproblems, degeneration of cartilage, osteoarthritis, and reproductivehealth complications of obesity or overweight such as infertility.

The invention also provides a GOAT inhibitor of the invention for use ina method of prevention or treatment of Alzheimer's disease, diabetes,type 1 diabetes, type 2 diabetes, pre-diabetes, insulin resistancesyndrome, impaired glucose tolerance (IGT), disease states associatedwith elevated blood glucose levels, metabolic disease includingmetabolic syndrome, hyperglycemia, hypertension, atherogenicdyslipidemia, hepatic steatosis (“fatty liver”; including non-alcoholicfatty liver disease (NAFLD), which itself includes non-alcoholicsteatohepatitis (NASH)), kidney failure, arteriosclerosis (e.g.atherosclerosis), macrovascular disease, microvascular disease, diabeticheart (including diabetic cardiomyopathy and heart failure as a diabeticcomplication) coronary heart disease, peripheral artery disease orstroke.

The invention also provides a GOAT inhibitor of the invention for use ina method of lowering circulating LDL levels and/or increasing HDL/LDLratio.

Effects of GOAT inhibitors on these conditions may be mediated in wholeor in part via an effect on body weight, or may be independent thereof.

The invention further provides use of a GOAT inhibitor of the inventionin the manufacture of a medicament for treating, inhibiting or reducingweight gain, promoting weight loss and/or reducing excess body weight.

The invention also provides use of a GOAT inhibitor of the invention inthe manufacture of a medicament for treating obesity as well asassociated diseases, disorders and health conditions, including, but notlimited to, morbid obesity, obesity prior to surgery, obesity-linkedinflammation, obesity-linked gallbladder disease and obesity-inducedsleep apnea and respiratory problems, degeneration of cartilage,osteoarthritis, and reproductive health complications of obesity oroverweight such as infertility.

The invention also provides use of a GOAT inhibitor of the invention inthe manufacture of a medicament for the prevention or treatment ofAlzheimer's disease, diabetes, type 1 diabetes, type 2 diabetes,pre-diabetes, insulin resistance syndrome, impaired glucose tolerance(IGT), disease states associated with elevated blood glucose levels,metabolic disease including metabolic syndrome, hyperglycemia,hypertension, atherogenic dyslipidemia, hepatic steatosis (“fattyliver”; including non-alcoholic fatty liver disease (NAFLD), whichitself includes non-alcoholic steatohepatitis (NASH)), kidney failure,arteriosclerosis (e.g. atherosclerosis), macrovascular disease,microvascular disease, diabetic heart (including diabetic cardiomyopathyand heart failure as a diabetic complication) coronary heart disease,peripheral artery disease or stroke.

The invention also provides use of a GOAT inhibitor of the invention inthe manufacture of a medicament for lowering circulating LDL levelsand/or increasing HDL/LDL ratio.

The invention further provides a method of treating, inhibiting orreducing weight gain, promoting weight loss and/or reducing excess bodyweight in a subject, comprising administering a therapeuticallyeffective amount of a GOAT inhibitor of the invention to the subject.

The invention also provides a method of treating obesity as well asassociated diseases, disorders and health conditions, including, but notlimited to, morbid obesity, obesity prior to surgery, obesity-linkedinflammation, obesity-linked gallbladder disease and obesity-inducedsleep apnea and respiratory problems, degeneration of cartilage,osteoarthritis, and reproductive health complications of obesity oroverweight such as infertility in a subject, comprising administering atherapeutically effective amount of a GOAT inhibitor of the invention tothe subject.

The invention also provides a method of prevention or treatment ofAlzheimer's disease, diabetes, type 1 diabetes, type 2 diabetes,pre-diabetes, insulin resistance syndrome, impaired glucose tolerance(IGT), disease states associated with elevated blood glucose levels,metabolic disease including metabolic syndrome, hyperglycemia,hypertension, atherogenic dyslipidemia, hepatic steatosis (“fattyliver”; including non-alcoholic fatty liver disease (NAFLD), whichitself includes non-alcoholic steatohepatitis (NASH)), kidney failure,arteriosclerosis (e.g. atherosclerosis), macrovascular disease,microvascular disease, diabetic heart (including diabetic cardiomyopathyand heart failure as a diabetic complication) coronary heart disease,peripheral artery disease or stroke in a subject, comprisingadministering a therapeutically effective amount of a GOAT inhibitor ofthe invention to the subject.

The invention further provides a method of lowering circulating LDLlevels and/or increasing HDL/LDL ratio in a subject, comprisingadministering a therapeutically effective amount of a GOAT inhibitor ofthe invention to the subject.

The invention further provides the use of a GOAT inhibitor as describedabove in a method of cosmetic (i.e. non-therapeutic) weight loss. Itwill be understood that references to therapeutic uses of GOATinhibitors and methods comprising administration of GOAT inhibitors mayequally be taken to encompass uses and administration of suchcompositions.

Further aspects and embodiments of the present invention will becomeapparent from the disclosure below.

The dose range of the compounds of general formula I applicable per dayis usually from 0.001 to 10 mg per kg body weight, for example from 0.01to 8 mg per kg body weight of the patient. Each dosage unit mayconveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the compound or composition will be administered atdosages and in a manner which allows a therapeutically effective amountto be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to the skilled man on thebasis of his specialist knowledge. The preferred ones are those that aresuitable for the particular formulation and method of administrationthat are desired. The preparations or formulations according to theinvention may be prepared using methods known per se that are familiarto the skilled man, such as for example by mixing or combining at leastone compound of formula I according to the invention, or apharmaceutically acceptable salt of such a compound, and one or moreexcipients, carriers and/or diluents.

Combination Therapy

A compound of the invention may be administered as part of a combinationtherapy together with another active agent for the treatment of thedisease or disorder in question, e.g. an anti-diabetic agent, ananti-obesity agent, an agent for treatment of metabolic syndrome, ananti-dyslipidemia agent, an anti-hypertensive agent, a proton pumpinhibitor, or an anti-inflammatory agent. In such cases, the two activeagents may be given together or separately, e.g. as constituents in thesame pharmaceutical composition or formulation, or as separateformulations.

Thus a compound of the invention may have some benefit if administeredin combination with an anti-diabetic agent of known type, including, butnot limited to, metformin, a sulfonylurea, a glinide, a DPP-IVinhibitor, a glitazone, a GLP-1 receptor agonist (including GLP-1 or aGLP-1 analogue, an exendin-4 or an exendin-4 analogue, any other GLP-1receptor agonist including liraglutide (Saxenda™, Victoza™), Dulaglutideor Albiglutide or a glucagon-GLP-1 dual agonist, e.g. as described inWO2008/101017, WO2008/152403, WO2010/070252, WO2010/070253,WO2010/070255, WO2010/070251, WO2011/006497, WO2011/160630,WO2011/160633, WO2013/092703, WO2014/041195), an SGLT2 inhibitor (i.e.an inhibitor of sodium-glucose transport, e.g. a gliflozin such asempagliflozin, canagliflozin, dapagliflozin or ipragliflozin), a GPR40agonist (FFAR1/FFA1 agonist, e.g. fasiglifam), or an insulin or aninsulin analogue. Examples of appropriate insulin analogues include, butare not limited to, Lantus™ Novorapid™, Humalog™, Novomix™, Actraphane™HM, Levemir™ Degludec™ and Apidra™. Other relevant anti-diabetic agentsin this connection include GLP-1 receptor agonists, such as exenatide(Byetta™ and Bydureon™ exendin-4) and Byetta LAR™, lixisenatide(Lyxumia™) and liraglutide (Victoza™).

Moreover, a compound of the invention may be used in combination with ananti-obesity agent of known type, including, but not limited to, peptideYY or an analogue thereof, neuropeptide Y (NPY) or an analogue thereof,a cannabinoid receptor 1 antagonist, a lipase inhibitor, Human prolsletPeptide (HIP), a melanocortin receptor 4 agonist, a GLP-1 receptoragonist (including GLP-1 or a GLP-1 analogue, an exendin-4 or anexendin-4 analogue, any other GLP-1 receptor agonist includingliraglutide (Saxenda™, Victoza™), Dulaglutide or Albiglutide or aglucagon-GLP-1 dual agonist, e.g. as described in WO2008/101017,WO2008/152403, WO2010/070252, WO2010/070253, WO2010/070255,WO2010/070251, WO2011/006497, WO2011/160630, WO2011/160633,WO2013/092703, WO2014/041195), Orlistat™, Sibutramine™, phentermine, amelanin concentrating hormone receptor 1 antagonist, CCK, amylin,pramlintide and leptin, as well as analogues thereof.

A compound of the invention may further be used in combination with ananti-hypertension agent of a known type, including, but not limited to,an angiotensin-converting enzyme inhibitor, an angiotensin II receptorblocker, a diuretic, a beta-blocker and a calcium channel blocker.

A compound of the invention may still further be used in combinationwith an anti-dyslipidemia agent of known type, including, but notlimited to, a statin, a fibrate, a niacin, a PSCK9 (Proproteinconvertase subtilisin/kexin type 9) inhibitor, and a cholesterolabsorption inhibitor.

A compound of the invention may also be used in combination with aproton pump inhibitor (i.e. a pharmaceutical agent possessingpharmacological activity as an inhibitor of H⁺/K⁺-ATPase) of known type,including, but not limited to, an agent of the benzimidazole derivativetype or of the imidazopyridine derivative type, such as Omeprazole™,Lansoprazole™, Dexlansoprazole™, Esomeprazole™ Pantoprazole™,Rabeprazole™, Zolpidem™, Alpidem™, Saripidem™ or Necopidem™.

In addition, with regard to anti-inflammatory treatment, a compound ofthe invention may be beneficial if administered in combination with ananti-inflammatory agent of known type, including, but not limited to:

steroids and corticosteroids, such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone;

non-steroidal anti-inflammatory agents (NSAIDs), such as propionic acidderivatives (e.g. alminoprofen, benoxaprofen, bucloxic acid, carprofen,fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen,ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen,suprofen, tiaprofenic acid and tioxaprofen); acetic acid derivatives(e.g. indomethacin, acemetacin, alclofenac, clidanac, diclofenac,fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac,oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac);fenamic acid derivatives (e.g. flufenamic acid, meclofenamic acid,mefenamic acid, niflumic acid and tolfenamic acid); biphenylcarboxylicacid derivatives (e.g. diflunisal and flufenisal); oxicams (e.g.isoxicam, piroxicam, sudoxicam and tenoxicam); salicylates (e.g.acetylsalicylic acid and sulfasalazine); and pyrazolones (e.g. apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone andphenylbutazone);

COX II inhibitors, such as rofecoxib and celecoxib; preparations ofinterferon beta (e.g. interferon beta-1 a or interferon beta-1 b);

and certain other compounds, such as 5-aminosalicylic acid and prodrugsand pharmaceutically acceptable salts thereof.

Metformin has also been demonstrated to have anti-inflammatoryproperties (see, e.g., Haffner et al., Diabetes 54: 1566-1572 (2005))and as such may also be useful in combination with compounds of theinvention.

The dosage for the combination partners mentioned above is usually ⅕ ofthe lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Preferably, compounds of the present invention and/or pharmaceuticalcompositions comprising a compound of the present invention optionallyin combination with one or more additional therapeutic agents areadministered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment of diseases or conditions which may be affected or whichare mediated by the inhibition of ghrelin O-acyl transferase (GOAT), inparticular diseases or conditions as described hereinbefore andhereinafter.

In yet another aspect the present invention relates a method fortreating a disease or condition mediated by the inhibition of ghrelinO-acyl transferase (GOAT) in a patient that includes the step ofadministering to the patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention in combination with a therapeutically effective amountof one or more additional therapeutic agents described in hereinbeforeand hereinafter,

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention and one or more additional therapeutic agents describedhereinbefore and hereinafter, optionally together with one or more inertcarriers and/or diluents.

Other features and advantages of the present invention will becomeapparent from the following more detailed Examples which illustrate, byway of example, the principles of the invention.

EXAMPLES

The following examples serve to further explain the invention withoutrestricting it.

The hereinafter described compounds have been characterized throughtheir characteristic mass after ionisation in a mass-spectrometer and/ortheir retention time on an analytical HPLC.

HPLC Methods:

Method 1: Column: Waters XBridge C18, 3 × 30 mm, 2.5 μm Detection:Agilent 1200 with DA- and MS-Detector Eluent A: Water (0.1% NH₃); EluentB: Acetonitrile Gradient: Time (min.) % Eluent B Flow [mL/min] Temp [°C.] 0.00 3 2.2 60 0.20 3 2.2 60 1.20 100 2.2 60 1.25 100 3.0 60 1.40 1003.0 60

Method 2: Column: Waters SunFire, 3 × 30 mm, 2.5 μm Detection: Agilent1200 with DA- and MS-Detector Eluent A: Water (0.1% Trifluoroaceticacid); Eluent B: Acetonitrile Gradient: Time (min.) % Eluent B Flow[mL/min] Temp [° C.] 0.00 3 2.2 60 0.20 3 2.2 60 1.20 100 2.2 60 1.25100 3.0 60 1.40 100 3.0 60

Method 3: Column: Waters SunFire C18, 3 × 30 mm, 2.5 μm Detection:Agilent 1200 with DA- and MS-Detector Eluent A: Water (0.1% Formicacid); Eluent B: Acetonitrile Gradient: Time (min.) % Eluent B Flow[mL/min] Temp [° C.] 0.00 3 2.2 60 0.20 3 2.2 60 1.20 100 2.2 60 1.25100 3.0 60 1.40 100 3.0 60

Method 4: Column: Waters XBridge C18, 3 × 30 mm, 2.5 μm Detection:Agilent 1200 with DA- and MS-Detector Eluent A: Water (0.1% Formicacid); Eluent B: Acetonitrile Gradient: Time (min.) % Eluent B Flow[mL/min] Temp [° C.] 0.00 3 2.2 60 0.20 3 2.2 60 1.20 100 2.2 60 1.25100 3.0 60 1.40 100 3.0 60

Method 5: Column: Waters XBridge C18, 3 × 30 mm, 2.5 μm Detection:Agilent 1100 with DAD, CTC Autosampler and Waters MS-Detector Eluent A:Water (0.1% NH₄OH); Eluent B: Acetonitrile Gradient: Time (min.) %Eluent B Flow [mL/min] Temp [° C.] 0.00 2 2.0 60 1.20 100 2.0 60 1.40100 2.0 60

Method 10: Column: Waters XBridge C18, 3.0 × 30 mm, 2.5 μm Detection:Waters Acquity with 3100 MS Eluent A: Water (0.1% NH₄OH); Eluent B:Acetonitrile Gradient: Time (min.) % Eluent B Flow [mL/min] Temp [° C.]0.00 5 1.5 60 1.30 99.0 1.5 60 1.50 99.0 1.5 60

Method 12: XBridge C18_3.0 × 30 mm, 2.5 μm Detection: Agilent 1200 withDA- and MS-Detector Eluent A: Water (0.1% TFA); Eluent B: AcetonitrileGradient: Time (min.) % Eluent B Flow [mL/min] Temp [° C.] 0.00 3 2.2 600.20 3 2.2 60 1.20 0 2.2 60 1.25 0 2.2 60 1.40 0 2.2 60

Method 13: Sunfire C18_3.0 × 30 mm, 2.5 μm Detection: Waters Acquity,QDa Detector Eluent A: Water (0.1% TFA); Eluent B: Acetonitrile (0.08%TFA) Gradient: Time (min.) % Eluent B Flow [mL/min] Temp [° C.] 0.00 51.5 40 1.30 100 1.5 40 1.50 100 1.5 40 1.60 5 1.5 40

Preparation of the Starting Compounds:

A 7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-carboxylic AcidEthyl Ester

4-Amino-1,2,5-oxadiazole-3-carbonitrile (prepared according to Chemistryof Heterocyclic Compounds (New York, N.Y., United States), 1994, vol.30, #5 p. 608-611) (1.00 g, 9.08 mmol) and ethyl acetoacetate (1.15 mL,9.08 mmol) are dissolved in 10 mL of toluene. Tin(IV)chloride (2.13 mL,18.2 mmol) is added and the mixture is stirred at reflux for 30 minutes.The mixture is concentrated under reduced pressure and the residue isdiluted with NaHCO₃ (half saturated aqueous solution) and the aqueousphase is extracted with dichloromethane. The combined organic layers aredried and concentrated under reduced pressure.

Yield: 2.47 g (98% of theory)

Mass spectrometry (ESI⁺): m/z=223 [M+H]+

HPLC (Method 1): Retention time=0.85 min.

B 7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethanol

The reaction is carried out under an argon atmosphere. A mixture of7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-carboxylic acid ethylester A (1.00 g, 3.60 mmol) in 10 mL toluene and 5 mL tetrahydrofuran iscooled to −78° C. Sodium bis(2-methoxy ethoxy)aluminium hydride (65% intoluene; 1.13 mL, 3.78 mmol) is added. The mixture is allowed to warm upto room temperature. After stirring over night at room temperatureadditional sodium bis(2-methoxy ethoxy)aluminium hydride (65% intoluene, 1.13 mL, 3.78 mmol) is added. After stirring for further 1.5hours the mixture is diluted with sodium-potassium-tartrate (saturatedaqueous solution) and extracted twice with tetrahydrofuran/ethylacetate. The combined organic layers are dried and concentrated underreduced pressure. The residue is purified by RP-HPLC (modifier:trifluoroacetic acid).

Yield: 530 mg (81% of theory)

Mass spectrometry (ESI⁺): m/z=181 [M+H]⁺

HPLC (Method 3): Retention time=0.24 min.

C 6-Chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethanol B (30.0mg, 0.17 mmol) is taken up in 0.2 mL N,N-dimethylformamide.Thionylchloride (24 μL, 0.33 mmol) is slowly added dropwise. The mixtureis stirred for 20 minutes at room temperature and then concentratedunder reduced pressure.

Yield: 33.0 mg (100% of theory)

Mass spectrometry (ESI⁺): m/z=195 [M+H]⁺, corresponding to methyletheranalog upon adding methanol for HPLC analysis

HPLC (Method 2): Retention time=0.28 min.

D 6-(bromomethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amineHydrobromide

7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethanol B (541 mg,3.00 mmol) is dissolved in 30 mL of dichloromethane. Phosphorustribromide (0.10 mL, 1.05 mmol) is added dropwise and the mixture isstirred at room temperature for 4 days. The solid is filtered and washedwith dichloromethane.

Yield: 850 mg (88% of theory)

e 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl Acetate

7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethanol B (25.0 g,139 mmol) is suspended in 160 mL concentrated acetic acid and themixture is stirred at 100° C. for 1.5 hours. Tert-butyl-methyl-ether isadded at RT and the mixture is stirred for 1 hour. The solid is filteredand washed with tert-butyl-methyl-ether. The solid is dried at 50° C.under vacuum.

Yield: 23 g (75% of theory)

Mass spectrometry (ESI⁺): m/z=223 [M+H]⁺

HPLC (Method 3): Retention time=0.68 min.

F 7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylic Acid

7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-carboxylic acid ethylester A (5.00 g, 22.5 mmol) is dissolved in 45 mL tetrahydrofuran andsodium hydroxide (1 M aqueous solution) (34 mL, 34 mmol) is added. Themixture is stirred for 18 hours at room temperature. Hydrochloric acid(4 M aqueous solution) (8.4 ml, 34 mmol) is slowly added and the mixtureis concentrated under reduced pressure to afford a solid residue. Thissolid material is filtered, rinsed with water, and dried under reducedpressure.

Yield: 3.40 g (78% of theory)

Mass spectrometry (ESI⁺): m/z=195 [M+H]⁺

HPLC (Method 12): Retention time=0.20 min.

G 6-Iodo-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylic acid F(3.40 g, 17.5 mmol) is dissolved in 40 ml N,N-dimethylformamide, sodiumbicarbonate (1.77 g, 21.0 mmol) and N-iodosuccinimide (4.73 g, 21.0mmol) are then sequentially added. The mixture is stirred for 18 hoursat room temperature and then concentrated under reduced pressure. Theresidue is diluted with water and stirred for 10 minutes. The mixture isfiltered to collect the solid material that is washed with water anddried under reduced pressure.

Yield: 4.65 g (96% of theory)

Mass spectrometry (ESI⁺): m/z=277 [M+H]⁺

HPLC (Method 12): Retention time=0.67 min.

2.1 2-Iodo-5-trifluoromethyl-isonicotonitrile

2-Chloro-5-trifluoromethyl-isonicotonitrile (3.30 g, 16.0 mmol) isdissolved in 20 ml dichloromethane and cooled to 0° C. Hydriodic acid(57% in water, 1.58 mL, 12.0 mmol) is added and the mixture is stirredfor 48 hours. The mixture is washed with half saturated aqueouspotassium carbonate and sodium thiosulfate solutions and then washedwith concentrated aqueous sodium chloride solution. The organic layer isdried, concentrated under reduced pressure and purified by RP-HPLC.

Yield: 2.82 g (28% of theory)

Mass spectrometry (ESI⁺): m/z=299 [M+H]⁺

HPLC (Method 3): Retention time=1.01 min.

4.1 6-Iodo-nicotinonitrile

2-Bromo-5-cyanopyridine (purchased from Apollo-Inter) (7.50 g, 41.0mmol) is dissolved in 75 mL dioxane. Copper (I)iodide (1.56 g, 8.20mmol) and sodium iodide (15.4 g, 103 mmol) are added and the mixture isstirred for 10 minutes. N,N′-Dimethylethylendiamine (1.75 mL, 16.4 mmol)is added and the mixture is stirred at 130° C. for 18 hours. The mixtureis extracted with half saturated solution of sodium bicarbonate. Theaqueous phase is extracted with ethyl acetate. The organic phase isdried and concentrated under reduced pressure. The residue is purifiedby silica gel chromatography (eluent: cyclohexane/ethyl acetate110/0→70/30).

Yield: 6.60 g (70% of theory)

Mass spectrometry (ESI⁻): m/z=231 [M+H]⁺

HPLC (Method 3): Retention time=0.62 min.

6.1 2-Iodo-5-trifluoromethyl-pyridine

Analogously to example 4.1 obtained by starting from2-bromo-5-trifluoromethyl-pyridine (purchased from Aldrich).

Yield: 93% of theory

Mass spectrometry (ESI⁺): m/z=274 [M+H]⁺

HPLC (Method 3): Retention time=1.03 min.

9.1 5-Difluoromethyl-2-iodo-pyridine

Analogously to example 4.1 obtained by starting from2-bromo-5-difluoromethyl-pyridine (purchased from Manchester).

Yield: 97% of theory

Mass spectrometry (ESI⁻): m/z=256 [M+H]⁺

HPLC (Method 3): Retention time=0.91 min.

10.2 (6-Iodo-pyridin-3-yl)-acetic Acid Methyl Ester

Prepared as described in WO2008/71646 page 91

11.1 5-(1,1-Difluoro-ethyl)-2-iodo-pyridine

Analogously to example 4.1, obtained by starting from2-bromo-5-(1,1-difluoro-ethyl)-pyridine (purchased from Manchester).

Yield: 95% of theory

Mass spectrometry (ESI⁻): m/z=270 [M+H]⁺

HPLC (Method 3): Retention time=1.00 min.

12.1 5-Fluoro-2-iodo-pyridine

Analogously to example 4.1 obtained by starting from2-bromo-5-fluoro-pyridine (purchased from Aldrich).

Yield: 83% of theory

HPLC (Method 3): Retention time=0.86 min.

13.1 2-Fluoro-6-iodo-pyridine

Analogously to example 4.1 obtained by starting from2-bromo-6-fluoro-pyridine (purchased from ABCR).

Yield: 85% of theory

HPLC (Method 3): Retention time=0.90 min.

14.2 5-Difluoromethoxy-2-iodo-pyridine

14.1 2-Bromo-5-difluoromethoxy-pyridine

6-Bromo-pyridin-3-ol (purchased from ABCR) (0.50 g, 2.87 mmol), sodiumchloro-difluoro-acetate (0.88 g, 5.75 mmol) and potassium carbonate(0.50 g, 3.59 mmol) are dissolved in 5 ml N,N-Dimethylformamide andstirred at 80° C. for 18 hours. Water is added and the mixture isextracted with diethyl ether twice. The organic phase is dried andconcentrated under reduced pressure. The mixture is purified by silicagel chromatography (eluent: cyclohexane/ethyl acetate 5%→15%).

Yield: 0.23 g (35% of theory)

Mass spectrometry (ESI⁻): m/z=224, 226 [M+H]⁺

HPLC (Method 3): Retention time=0.93 min.

14.2 5-Difluoromethoxy-2-iodo-pyridine

Analogously to example 4.1 obtained by starting from2-bromo-5-difluoromethoxy-pyridine 14.1.

Yield: 99% of theory

Mass spectrometry (ESI⁻): m/z=272 [M+H]⁺

HPLC (Method 2): Retention time=0.99 min.

15.2 2-Bromo-3-difluoromethoxy-6-iodo-pyridine

15.1 2-Bromo-6-iodo-pyridin-3-ol

2-Bromo-pyridin-3-ol (purchased from Aldrich) (1.00 g, 5.75 mmol) isdissolved in 13 mL water, potassium carbonate (1.51 g, 10.9 mmol) isadded and the mixture is stirred until it becomes homogeneous. Solidiodine (1.58 g, 6.21 mmol) is added and the mixture is stirred at 100°C. for 18 hours. The mixture is cooled to room temperature, acidifiedwith hydrochloric acid (1N aqueous solution) and extracted with ethylacetate. The organic fractions are dried with sodium sulfate andconcentrated.

Yield: 82% of theory

Mass spectrometry (ESI⁻): m/z=299, 301 [M+H]⁺

HPLC (Method 3): Retention time=0.85 min.

15.2 2-Bromo-3-difluoromethoxy-6-iodo-pyridine

Analogously to intermediate 14.1 obtained by starting from2-bromo-6-iodo-pyridin-3-ol 15.1 and sodium chlorodifluoro-acetate.Caesium carbonate is used instead of potassium carbonate.

Yield: 98% of theory

Mass spectrometry (ESI⁻): m/z=349, 351 [M+H]⁺

HPLC (Method 3): Retention time=1.04 min.

16.1 2-Iodo-6-methylsulfanyl-pyridine

Analogously to example 4.1, obtained by starting from2-bromo-6-(methylthio)pyridine (purchased from Activate). The reactionmixture is stirred at 110° C. for 20 hours. Ammonia (32% solution inwater, 40 mL) is then added and the reaction is poured into water andextracted with dichloromethane, dried with sodium sulfate andconcentrated under reduced pressure.

Yield: 92% of theory

HPLC (Method 3): Retention time=1.08 min.

19.2 3-Bromo-2-chloro-6-iodo-pyridine

19.1 5-Bromo-6-chloro-pyridin-2-ylamine

6-chloro-pyridin-2-ylamine (purchased from Aldrich) (1.50 g, 11.7 mmol)is dissolved in 15 ml N,N-Dimethylformamide and cooled to 5° C.1-bromo-pyrrolidine-2,5-dione (2.28 g, 12.8 mmol) is added and themixture is slowly warmed to room temperature. The mixture is poured ontoice water and the precipitate is collected by filtration and dried undervacuum.

Yield: 91% of theory

Mass spectrometry (ESI⁻): m/z=207, 209 [M+H]⁺

HPLC (Method 4): Retention time=0.87 min.

19.2 3-Bromo-2-chloro-6-iodo-pyridine

5-Bromo-6-chloro-pyridin-2-ylamine 19.1 (2.00 g, 9.64 mmol) is dissolvedin 20 mL tetrahydrofuran, copper(I) iodide (2.75 g, 14.5 mmol) is addedand diiodomethane (6.2 ml, 77.1 mmol) and tert-butyl nitrite (4.59 ml,38.6 mmol) are added. The mixture is stirred under reflux for 1 hour,and then it is cooled to room temperature and concentrated. The residueis dissolved in ethyl acetate and extracted with 10% aqueous solution ofsodium thiosulfate and saturated aqueous solution of sodium bicarbonate.The organic phase is washed with brine, dried and concentrated underreduced pressure. The mixture is purified by silica gel chromatography(eluent: cyclohexane/ethyl acetate 0%→5%).

Yield: 1.80 g (58% of theory)

Mass spectrometry (ESI⁻): m/z=318 [M+H]⁺

HPLC (Method 4): Retention time=1.00 min.

20.1 4-Chloro-2-iodo-5-trifluoromethyl-pyridine

2,4-dichloro-5-trifluoromethyl-pyridine (purchased from Manchester)(1.00 g, 4.63 mmol) is dissolved in 6.0 mL acetonitrile. Sodium iodide(694 mg, 4.63 mmol) and acetyl chloride (329 μL, 4.63 mmol) are addedand the mixture is stirred at room temperature for 3.5 hours. Themixture is diluted with ethyl acetate, washed with half saturatedsolutions of sodium bicarbonate and sodium thiosulfate, dried andconcentrated under reduced pressure. The residue is purified bypreparative RP-HPLC (modifier: trifluoroacetic acid).

Yield: 220 mg (15% of theory)

HPLC (Method 4): Retention time=1.02 min.

21.2 2,3-Dibromo-6-iodo-pyridine

5,6-Dibromo-pyridin-2-ylamine is prepared as described in WO2005/100353page 21

21.2 2,3-Dibromo-6-iodo-pyridine

Analogously to example 19.2, obtained by starting from5,6-dibromo-pyridin-2-ylamine and tert-butyl nitrite.

Yield: 80% of theory

22.2 3-Bromo-2-fluoro-6-iodo-pyridine

22.1 5-Bromo-6-fluoro-pyridin-2-ylamine

Analogously to example 19.1, obtained by starting from6-fluoro-pyridin-2-ylamine (purchased from Activate) and1-bromo-pyrrolidine-2,5-dione.

Yield: 60% of theory

Mass spectrometry (ESI⁻): m/z=191, 193 [M+H]⁺

HPLC (Method 4): Retention time=0.75 min.

22.2 3-Bromo-2-fluoro-6-iodo-pyridine

Analogously to example 19.2 obtained by starting from5-bromo-6-fluoro-pyridin-2-ylamine 22.1 and tert-butyl nitrite.

Yield: 61% of theory

Mass spectrometry (ESI⁻): m/z=301, 303 [M+H]⁺

HPLC (Method 4): Retention time=0.96 min.

23.3 3-Bromo-2-difluoromethoxy-6-iodo-pyridine

23.1 6-Difluoromethoxy-pyridin-2-ylamine

Analogously to intermediate 14.1 obtained by starting from6-amino-pyridin-2-ol (purchased from Acros) and sodiumchloro-difluoro-acetate. Stirred for 18 hours at 100° C., extracted withethyl acetate and a half saturated aqueous solution of sodiumbicarbonate instead of diethyl ether. The organic phase is washed withbrine, dried and concentrated.

Yield: 64% of theory

Mass spectrometry (ESI⁻): m/z=161 [M+H]⁺

HPLC (Method 4): Retention time=0.71 min.

23.2 5-Bromo-6-difluoromethoxy-pyridin-2-ylamine

Analogously to example 19.1, obtained by starting from6-difluoromethoxy-pyridin-2-ylamine 23.1 and1-bromopyrrolidine-2,5-dione.

Yield: 94% of theory

Mass spectrometry (ESI⁻): m/z=240, 242 [M+H]⁺

HPLC (Method 4): Retention time=0.89 min.

23.3 3-Bromo-2-difluoromethoxy-6-iodo-pyridine

Analogously to example 19.2 obtained by starting from5-bromo-6-difluoromethoxy-pyridin-2-ylamine 23.2 and tert-butyl nitrite.

Yield: 34% of theory

HPLC (Method 4): Retention time=1.04 min.

24.3 2-Chloro-6-iodo-nicotinonitrile

24.1 6-Chloro-5-iodo-pyridin-2-ylamine

Analogously to example 19.1, obtained by starting from6-chloro-pyridin-2-ylamin (purchased from Aldrich), addN-iodosuccinimide at room temperature (temperature rise until 80° C.)and stirred for 15 minutes. The mixture is poured onto ice water and theprecipitate is filtered and dried under vacuum.

Yield: 94% of theory

Mass spectrometry (ESI⁻): m/z=255 [M+H]⁺

HPLC (Method 12): Retention time=0.82 min.

24.2 6-Amino-2-chloro-nicotinonitrile

6-Chloro-5-iodo-pyridin-2-ylamine 24.1 (4.00 g, 15.7 mmol) is dissolvedin 15 mL N,N-dimethylformamide, zinc cyanide (0.997 g, 8.50 mmol) isadded and the mixture is vigorously stirred while purging the mixturewith an argon stream for 5 min. (Tris(dibenzylideneacetone)-dipalladium(0) (0.642 g, 0.701 mmol) and 1,1′-bis(diphenylphosphino) ferrocene(0.784 g, 1.42 mmol) are added and stirred for 10 minutes at 120° C. Themixture is extracted with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The organic phase is filtered oversilica gel and concentrated. The mixture is purified by silica gelchromatography (eluent: cyclohexane/ethyl acetate 100/0→50/50).

Yield: 1.60 g (66% of theory)

Mass spectrometry (ESI⁺): m/z=154 [M+H]⁺

HPLC (Method 1): Retention time=0.60 min

24.3 2-Chloro-6-iodo-nicotinonitrile

Analogously to example 19.2 obtained by starting from6-Amino-2-chloro-nicotinonitrile 24.2 and tert-butyl nitrite.

Yield: 60% of theory

HPLC (Method 4): Retention time=0.87 min.

25.3 3-Fluoro-6-iodo-pyridine-2-carbonitrile

25.1 2-Bromo-5-fluoro-pyridine 1-oxide

2-bromo-5-fluoro-pyridine (purchased from Activate) (8.60 g, 48.9 mmol)is dissolved in 75 mL dichloromethane, then cooled to 0° C. andtrifluoroacetic anhydride (20.4 ml, 147 mmol) is added. Hydrogenperoxide (30% aqueous solution, 5.9 ml, 58.6 mmol) is added dropwise andthe reaction stirred for 18 hours at room temperature. The mixture ispoured carefully on a diluted saturated aqueous solution of sodiumbicarbonate. The organic phase is separated, dried and concentratedunder reduced pressure.

Yield: 7.18 g (76% of theory)

Mass spectrometry (ESI⁺): m/z=192, 194 [M+H]⁺

HPLC (Method 12): Retention time=0.19 min

25.2 6-Bromo-3-fluoro-pyridine-2-carbonitrile

2-Bromo-5-fluoro-pyridine 1-oxide 25.1 (7.18 g, 37.4 mmol) and dimethylsulfate (3.9 ml, 41.1 mmol) are stirred at room temperature for 72 h.The residue is dissolved in 35 mL water and cooled to 0° C. To thisreaction mixture is added a prepared solution of sodium cyanide (7.45 g,146 mmol) in 35 ml water and the mixture is stirred for 20 minutes at 0°C. The solid is collected by filtration and dried under reducedpressure.

Yield: 6.38 g (85% of theory)

Mass spectrometry (ESI⁺): m/z=200, 202 [M+H]⁺

HPLC (Method 12): Retention time=0.79 min

25.3 3-Fluoro-6-iodo-pyridine-2-carbonitrile

Analogously to example 4.1 obtained by starting from6-Bromo-3-fluoro-pyridine-2-carbonitrile 25.2.

Yield: 74% of theory

Mass spectrometry (ESI⁻): m/z=248 [M+H]⁺

HPLC (Method 12): Retention time=0.83 min.

26.1 2-Iodo-4-trifluoromethyl-pyridine

Analogously to intermediate 20.1 obtained by starting from2-bromo-4-trifluoromethyl-pyridine (purchased from Activate), acetylchloride and sodium iodide.

Yield: 99% of theory

27.1 5-Bromo-2-iodo-isonicotinonitrile

Analogously to intermediate 20.1 obtained by starting from5-bromo-2-chloro-isonicotinonitrile (purchased from Apollo), acetylchloride and sodium iodide.

Yield: 86% of theory

HPLC (Method 3): Retention time=0.99 min.

28.1 2-Iodo-isonicotinonitrile

Analogously to intermediate 20.1 obtained by starting from2-bromo-isonicotinonitrile (purchased from Activate), acetyl chlorideand sodium iodide.

Yield: 87% of theory

29.2 2-Iodo-isonicotinamide

29.1 2-Iodo-isonicotinoyl chloride

To a solution of 2-iodoisonicotinic acid (purchased from Adesis) (0.750g, 3.01 mmol) dissolved in 10 ml of dichloromethane is addedoxalylchloride (0.284 ml, 3.31 mmol). The mixture is stirred at roomtemperature for 18 hours and used as such for next step.

Yield: 0.80 g (99% of theory)

29.2 2-Iodo-isonicotinamide

To the crude reaction solution containing 2-iodo-isonicotinoyl chloride29.1 (0.800 g, 2.99 mmol) in 10 mL dichloromethane is added ammoniasolution (32% aqueous solution, 1.59 g, 29.9 mmol), stirred for 30minutes and concentrated under reduced pressure.

Yield: 0.49 g (65% of theory)

32.2 5-Bromo-2-iodo-4-trifluoromethyl-pyridine

32.1 5-Bromo-4-trifluoromethyl-pyridin-2-ylamine

Analogously to example 19.1, obtained by starting from4-trifluoromethyl-pyridin-2-ylamine (purchased from Manchester) and1-bromo-pyrrolidine-2,5-dione. The mixture is poured into water,extracted with ethyl acetate and washed with a half saturated aqueoussolution of sodium bicarbonate. The organic phase is dried andconcentrated under reduced pressure.

Yield: 1.43 g (96% of theory)

Mass spectrometry (ESI⁻): m/z=240, 242 [M+H]⁺

32.2 5-Bromo-2-iodo-4-trifluoromethyl-pyridine

Analogously to example 19.2 obtained by starting from5-bromo-4-trifluoromethyl-pyridin-2-ylamine 32.1 and tert-butyl nitrite.

Yield: 60% of theory

33.3 6-Iodo-3-trifluoromethoxy-pyridine-2-carbonitrile

33.1 2-bromo-5-(trifluoromethoxy)pyridin-1-ium-1-olate Commerciallyavailable 2-bromo-5-(trifluoromethoxy)pyridine (Manchester) is dissolvedin 20 mL of dichloromethane and cooled to 0° C. Trifluoroacetic acidanhydride (2.26 mL, 16.1 mmol) and hydrogen peroxide (35% solution inwater, 0.941 mL, 10.7 mmol) are added and the mixture is stirred for 18hours. The reaction mixture slowly poured into saturated aqueous sodiumbicarbonate solution and extracted with dichloromethane. The combinedorganic phases are dried and concentrated under reduced pressure.

Yield: 1.40 g (100% of theory)

Mass spectrometry (ESI⁻): m/z=257, 259 [M+H]⁺

HPLC (Method 3): Retention time=0.728 min.

33.2 6-Bromo-(3-trifluoromethoxy)pyridine-2-carbonitrile

2-bromo-5-(trifluoromethoxy)pyridin-1-ium-1-olate 33.1 (1.40 g, 5.43mmol) is dissolved in 10 mL of acetonitrile. Triethylamine (1.14 mL, 8.1mmol) and trimethylsilylcyanide (1.46 mL, 10.8 mmol) are added and themixture is stirred at 80° C. for 40 hours. The mixture is diluted withethyl acetate, concentrated under reduced pressure and purified bychromatography on silica gel (using a solvent gradient ofcyclohexane/ethyl acetate from 100/0 to 80/20).

Yield: 0.80 _(g) (55% of theory)

Mass spectrometry (ESI⁻): m/z=266, 268 [M+H]⁺

HPLC (Method 3): Retention time=1.03 min.

33.3 6-Iodo-3-trifluoromethoxy-pyridine-2-carbonitrile

Analogously to example 4.1 obtained by starting from6-bromo-3-trifluoromethoxy-pyridine-2-carbonitrile 33.2 and stirred at110° C. for 20 hours. Ammonia (32% solution, 40 mL) is added and thereaction is poured into water and extracted with dichloromethane, driedwith sodium sulfate and concentrated under reduced pressure.

Yield: 94% of theory

Mass spectrometry (ESI⁻): m/z=315 [M+H]⁺

HPLC (Method 1): Retention time=0.99 min.

34.1 2-Iodo-4-trifluoromethyl-pyrimidine

Analogously to example 46.3 obtained by starting from2-bromo-4-trifluoromethyl-pyrimidine (purchased from Activate) andhydriodic acid (57% aqueous solution). The mixture is dissolved indioxane (5 mL) and stirred for 3 hours at 50° C. The mixture is thenextracted with ethyl acetate and washed with a half saturated aqueoussolution of sodium bicarbonate. The organic phases are washed with a 20%aqueous solution of sodium thiosulfate and a half saturated aqueoussolution of sodium chloride. The organic phases are dried andconcentrated.

Yield: 96% of theory

HPLC (Method 1): Retention time=0.90 min.

35.1 2-iodo-5-(trifluoromethyl)pyrimidine

Analogously to example 46.3, obtained by starting from2-chloro-5-(trifluoromethyl)pyrimidine (purchased from Manchester),sodium iodide and hydriodic acid (57% aqueous solution). The mixture isdissolved in dioxane (30 mL), stirred for 1 hour at 80° C., cooled toroom temperature and extracted with ethyl acetate and washed with a halfsaturated aqueous solution of sodium bicarbonate. The organic phases arewashed with a 20% aqueous solution of sodium thiosulfate and a halfsaturated aqueous solution of sodium chloride. The organic phases aredried and concentrated.

Yield: 100% of theory

36.1 6-iodo-4-(trifluoromethyl)pyridine-2-carbonitrile

Analogously to intermediate 20.1, obtained by starting from6-chloro-4-(trifluoromethyl)pyridine-2-carbonitrile (purchased fromArkpharma), acetyl chloride and sodium iodide. The mixture is stirred at50° C. for 18 hours. The mixture is poured into an aqueous solution ofsodium bicarbonate and extracted with dichloromethane. The organic phaseis dried and concentrated. The residue is purified by flash columnchromatography on silica gel (using a solvent gradient fromcyclohexane/ethyl acetate 100/0 to 90/10).

Yield: 66% of theory

Mass spectrometry (ESI⁻): m/z=299 [M+H]⁺

HPLC (Method 1): Retention time=0.98 min.

37.3 3-(difluoromethyl)-6-iodopyridine-2-carbonitrile

37.1 2-bromo-5-(difluoromethyl)pyridin-1-ium-1-olate

Analogously to example 33.1, obtained by starting from2-bromo-5-difluoromethyl-pyridine (purchased from Manchester).

Yield: 79% of theory

37.2 6-bromo-3-(difluoromethyl)pyridine-2-carbonitrile

To a solution of 2-bromo-5-(difluoromethyl)pyridin-1-ium-1-olate 37.1(10.0 g, 44.6 mmol) in 10 mL acetonitrile is added triethylamine (9.4ml, 67.0 mmol) and trimethylsilyl cyanide (12.0 ml, 89.3 mmol). Themixture is stirred at 80° C. for 18 hours, silica gel is added and thesolvent is concentrated under reduced pressure. The mixture is purifiedby silica gel chromatography (eluent: cyclohexane/ethyl acetate100/0→75/25).

Yield: 6.3 g (61% of theory)

37.3 3-(difluoromethyl)-6-iodopyridine-2-carbonitrile

Analogously to intermediate 20.1, obtained by starting from6-bromo-3-(difluoromethyl)pyridine-2-carbonitrile 37.2, acetyl chlorideand sodium iodide. The mixture is stirred at 50° C. for 30 minutes.Ethyl acetate is added and the mixture is washed with a halfconcentrated aqueous sodium bicarbonate solution, a 20% aqueous solutionof sodium thiosulfate solution and brine. The organic phase is dried andconcentrated.

Yield: 95% of theory

Mass spectrometry (ESI⁻): m/z=280 [M+H]⁺

38.1 4-chloro-6-iodopyridine-2-carbonitrile

Analogously to example 4.1, obtained by starting from6-bromo-4-chloropyridine-2-carbonitrile (purchased from Enamine) andstirred at 110° C. for 20 hours. Ammonia (32% in water, 40 mL) is addedand the reaction is diluted with water. The aqueous phase is extractwith dichloromethane, dried with sodium sulfate and concentrated underreduced pressure.

Yield: 95% of theory

39.1 5-cyclopropyl-2-iodopyridine

2-bromo-5-cyclopropylpyridine (purchased from CombiPhos) (500 mg, 2.52mmol) is dissolved in 5 mL of dioxane. Copper (I) iodide (96.2 mg, 0.50mmol), sodium iodide (946 mg, 6.31 mmol) andN,N′-dimethylethylenediamine (105 mg, 1.01 mmol) are added and themixture is stirred at 130° C. for 2 hours. Ethyl acetate is added andthe mixture is washed with half concentrated aqueous sodium bicarbonatesolution. The organic phase is dried and concentrated under reducedpressure.

Yield: 541 mg (87% of theory)

Mass spectrometry (ESI⁺): m/z=245 [M+H]⁺

HPLC (Method 2): Retention time=0.97 min.

40.2 5-cyclopropyl-2-iodopyridine-4-carbonitrile

40.1 2-chloro-5-cyclopropylpyridine-4-carbonitrile

Under an atmosphere of argon 5-bromo-2-chloropyridine-4-carbonitrile(purchased from Apollo) (100 mg, 0.46 mmol) is dissolved in 2.5 mL oftetrahydrofuran. 1,1′-Bis-(diphenylphosphino)-ferrocenedichloropalladium(11) (110 mg, 0.15 mmol) and cyclopropylzinc bromide (4.6 mL, 2.30 mmol)are added and the mixture is stirred at 50° C. for 18 hours. Thereaction is quenched with sodium bicarbonate solution and extracted withdichloromethane. The organic phase is dried and concentrated underreduced pressure. The residue is purified by flash column chromatographyon silica gel (using a solvent gradient from petrolether/ethyl acetate99/1 to 62/38).

Yield: 35 mg (43% of theory)

Mass spectrometry (ESI⁺): m/z=179 [M+H]⁺

HPLC (Method 2): Retention time=0.97 min.

40.2 5-cyclopropyl-2-iodopyridine-4-carbonitrile

Analogously to intermediate 20.1 obtained by starting from2-chloro-5-cyclopropylpyridine-4-carbonitrile 40.1, sodium iodide andacetyl chloride. The mixture is stirred at 80° C. for 4 hours. Ethylacetate is added and the mixture is washed with a half concentratedaqueous sodium bicarbonate solution and 20% aqueous solution of sodiumthiosulfate solution and washed with brine. The organic phase is driedand concentrated under reduced pressure. The residue is purified byRP-HPLC (modifier: formic acid)

Yield: 64% of theory

Mass spectrometry (ESI⁻): m/z=270 [M+H]⁺

HPLC (Method 2): Retention time=0.999 min.

41.2 5-cyclopropoxy-2-iodopyridine

41.1

5-cyclopropoxy-2-chloropyridine was prepared as described inWO2014/114578 page 99 and 101

41.2 5-cyclopropoxy-2-iodopyridine

Analogously to intermediate 20.1 obtained by starting from2-chloro-5-cyclopropoxypyridine 41.1, sodium iodide and acetyl chloridein acetonitrile. The mixture is stirred at 80° C. for 2 days. Ethylacetate is added and the mixture is washed with a half concentratedaqueous sodium bicarbonate solution, a 10% aqueous sodium thiosulfatesolution and brine. The organic phase is dried and concentrated. Theresidue is purified by RP-HPLC (modifier: formic acid)

Yield: 8% of theory

Mass spectrometry (ESI⁻): m/z=261 [M+H]⁺

HPLC (Method 2): Retention time=0.99 min.

42.2 3-cyclopropyl-6-iodopyridine-2-carbonitrile

42.1 6-chloro-3-cyclopropylpyridine-2-carbonitrile

Analogously to example 40.1 obtained by starting from3-bromo-6-chloro-pyridine-2-carbonitrile (from Aldrich).

Yield: 1.44 g (87% of theory)

Mass spectrometry (ESI⁺): m/z=179 [M+H]⁺

HPLC (Method 1): Retention time=0.98 min.

42.2 3-cyclopropyl-6-iodopyridine-2-carbonitrile

Analogously to intermediate 20.1 obtained by starting from6-chloro-3-cyclopropylpyridine-2-carbonitrile 42.1, sodium iodide andacetyl chloride in acetonitrile. The mixture is stirred at 80° C. for 2days. Ethyl acetate is added and the mixture is washed with a halfconcentrated aqueous sodium bicarbonate solution, a 10% aqueous sodiumthiosulfate solution and brine. The organic phase is dried andconcentrated under reduced pressure. The residue is purified bychromatography on silica gel (using a solvent gradient fromcyclohexane/ethyl acetate 94/6 to 84/16).

Yield: 29% of theory

Mass spectrometry (ESI⁻): m/z=270 [M+H]⁺

HPLC (Method 1): Retention time=0.99 min.

43.3 2-cyclopropyl-6-iodopyridine-3-carbonitrile

43.1 6-chloro-2-iodopyridine-3-carbonitrile was prepared as described inUS2016/0075704 paragraph 287-289 43.26-chloro-2-cyclopropylpyridine-3-carbonitrile

Analogously to example 40.1 obtained by starting from6-chloro-2-iodopyridine-3-carbonitrile 43.1.

Yield: 926 mg (69% of theory)

Mass spectrometry (ESI⁺): m/z=179 [M+H]⁺

HPLC (Method 2): Retention time=1.04 min.

43.3 2-cyclopropyl-6-iodopyridine-3-carbonitrile

Analogously to intermediate 20.1 obtained by starting from6-chloro-2-cyclopropylpyridine-3-carbonitrile 43.2, sodium iodide andacetyl chloride in acetonitrile. The mixture is stirred at 80° C. for 2days. Ethyl acetate is added and the mixture is washed with a halfconcentrated aqueous sodium bicarbonate solution, a 10% solution ofsodium thiosulfate solution and brine. The organic phase is dried andconcentrated under reduced pressure. The residue is purified bychromatography on silica gel (using a solvent gradient frompetrolether/dichloromethane 92/8 to 53/47).

Yield: 118 mg (9% of theory)

Mass spectrometry (ESI⁻): m/z=270 [M+H]⁺

HPLC (Method 1): Retention time=1.06 min.

44.1 2-Iodo-5-methylsulfanyl-pyridine

Analogously to example 4.1, obtained by starting from2-Bromo-5-(methylthio)pyridine (from Chembridge). The reaction mixtureis stirred at 110° C. for 20 hours. Ammonia (32% solution, 40 mL) isadded, the reaction is poured into water and extracted withdichloromethane. The organic phase is dried and concentrated underreduced pressure.

Yield: 97% of theory

Mass spectrometry (ESI⁻): m/z=252 [M+H]⁺

HPLC (Method 1): Retention time=0.93 min.

45.2 (E)-N′-(5-cyano-2-iodopyrimidin-4-yl)-N,N-dimethylmethanimidamide

45.1 4-amino-2-iodopyrimidine-5-carbonitrile

4-Amino-2-chloropyrimidine-5-carbonitrile (from Alfa) (0.80 g, 5.18mmol) is dissolved in 8 mL of acetonitrile. Iodotrimethylsilane (0.7 mL,5.18 mmol) is added and the mixture is stirred at 80° C. for 4 hours.Ethyl acetate is added and the mixture is washed with a concentratedaqueous sodium bicarbonate solution. The organic phase is dried andconcentrated under reduced pressure.

Yield: 1.0 g (81% of theory)

Mass spectrometry (ESI⁺): m/z=247 [M+H]⁺

45.2 (E)-N′-(5-cyano-2-iodopyrimidin-4-yl)-N,N-dimethylmethanimidamide

Analogously to example 164.1 obtained by starting from4-amino-2-iodopyrimidine-5-carbonitrile 45.1. The mixture is stirred for2 hours. Ethyl acetate is added and the mixture is washed with a halfconcentrated aqueous sodium bicarbonate solution. The organic phase isdried and concentrated under reduced pressure.

Yield: 490 mg (80% of theory)

46.3 2-iodo-5-(trifluoromethyl)pyrimidin-4-amine

46.1 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine

2,4-dichloro-5-(trifluoromethyl)pyrimidine (from Tosch) (40.0 g, 184mmol) is dissolved in 300 mL of tetrahydrofuran and the mixture iscooled to 0° C. Ammonia (32% in water; 30.0 mL, 496 mmol) is addeddropwise and the mixture is stirred at room temperature for 18 hours.Ethyl acetate is added and the reaction mixture is washed with asaturated aqueous sodium bicarbonate solution. The organic phase isconcentrated under reduced pressure and purified by chromatography onsilica gel (using a solvent gradient of cyclohexane/ethyl acetate from100/0 to 50/50).

Yield: 17.6 g (48% of theory)

Mass spectrometry (ESI⁺): m/z=198 [M+H]⁺

HPLC (Method 4): Retention time=0.69 min.

46.2 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine

Obtained as a side-product using2,4-dichloro-5-(trifluoromethyl)pyrimidine and ammonia.

Yield: 18.6 g (48% of theory)

Mass spectrometry (ESI⁺): m/z=198 [M+H]⁺

HPLC (Method 4): Retention time=0.81 min.

46.3 2-iodo-5-(trifluoromethyl)pyrimidin-4-amine

2-chloro-5-(trifluoromethyl)pyrimidin-4-amine 46.1 (3.00 g, 15.2 mmol)and sodium iodide (6.83 g, 45.6 mmol) are suspended in 30 mL dioxane.Hydriodic acid (57% aqueous solution; 1.76 mL, 15.2 mmol) is added andthe mixture is stirred at 50° C. for 30 minutes. Saturated aqueoussodium bicarbonate solution is added and the precipitate is collected byfiltration. The solid is purified by chromatography on silica gel (usinga solvent gradient from cyclohexane/ethyl acetate 100/0 to 80/20).

Yield: 1.90 g (43% of theory)

Mass spectrometry (ESI⁻): m/z=290 [M+H]⁺

HPLC (Method 1): Retention time=0.75 min.

50.1 4-chloro-2-iodo-5-(trifluoromethyl)pyrimidine

4-chloro-5-(trifluoromethyl)pyrimidin-2-amine 46.2 (5.00 g, 25.31 mmol)is dissolved in 5 mL acetonitrile. Diiodomethane (20.0 mL, 248.3 mmol)and tert-butylnitrite (6.02 mL, 50.62 mmol) are added and the mixture isstirred at 70° C. for 2 hours. The mixture is concentrated under reducedpressure, the residue is dissolved in ethyl acetate and washed with a10% aqueous sodium thiosulfate solution and a saturated aqueous sodiumbicarbonate solution. The organic phase is washed with brine, dried,concentrated under reduced pressure and purified by chromatography onsilica gel (using a solvent gradient of cyclohexane/ethyl acetate from100/0 to 80/20).

Yield: 3.74 g (48% of theory)

Mass spectrometry (ESI⁺): m/z=308 [M+H]⁺

HPLC (Method 4): Retention time=0.98 min.

47.1 3-chloro-6-iodopyridine-2-carbonitrile

Analogously to intermediate 20.1 obtained by starting from6-bromo-3-chloro-2-cyanopyridine (from Matrix), sodium iodide and acetylchloride in acetonitrile. Stirred 18 hours at 50° C. and cooled,extracted with ethyl acetate and washed with a half saturated aqueoussolution of sodium bicarbonate. The organic phases are extracted with a20% aqueous solution of sodium thiosulfate and a half saturated aqueoussolution of sodium chloride. The organic phases are dried andconcentrated under reduced pressure. The residue is purified by RP-HPLC(modifier: trifluoroacetic acid)

Yield: 45% of theory

Mass spectrometry (ESI⁻): m/z=265 [M+H]⁺

HPLC (Method 2): Retention time=0.98 min.

48.3 6-iodo-3-(trifluoromethyl)pyridine-2-carbonitrile

48.2

6-chloro-3-(trifluoromethyl)pyridine-2-carbonitrile was prepared asdescribed in US2008/275057 page 81

48.3 6-iodo-3-(trifluoromethyl)pyridine-2-carbonitrile

Analogously to intermediate 20.1, obtained by starting from6-chloro-3-(trifluoromethyl)pyridine-2-carbonitrile 48.2, acetylchloride and sodium iodide. The mixture is stirred at 50° C. for 3 days.Diethyl ether is added and the mixture is washed with a saturatedaqueous solution of sodium bicarbonate, a saturated aqueous solution ofsodium thiosulfate and a saturated aqueous solution of sodium chloride.

The organic phases are dried and concentrated under reduced pressure.

Yield: 59% of theory

Mass spectrometry (ESI⁻): m/z=299 [M+H]⁺

HPLC (Method 1): Retention time=0.97 min.

51.1 2-iodopyrimidine-4-carbonitrile

Analogously to example 46.3 obtained by starting from2-chloropyrimidine-4-carbonitrile (from Activate), sodium iodide andhydriodic acid (57% aqueous solution). The mixture is dissolved indioxane (15 mL) and stirred for 1.5 hours at 100° C. The mixture iscooled to room temperature, extracted with ethyl acetate and washed witha half saturated aqueous solution of sodium bicarbonate. The organicphases are washed a 20% aqueous solution of sodium thiosulfate and ahalf saturated aqueous solution of sodium chloride. The organic phasesare dried and concentrated. The residue is purified by flash columnchromatography on silica gel (using a solvent gradient fromcyclohexane/ethyl acetate 100/0 to 80/20).

Yield: 72% of theory

Mass spectrometry (ESI⁻): m/z=231 [M+H]⁺

HPLC (Method 1): Retention time=0.58 min.

Example 16-(5-Methoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

1.1 (5-methoxypyridin-2-yl)magnesium Chloride

Commercially available (from Activate) 2-iodo-5-methoxypyridine (0.50 g,2.13 mmol) is dissolved in 3.0 mL of tetrahydrofuran and the mixture iscooled to −40° C. Isopropyl-magnesium chloride lithiumchloride complex(1.3 M solution, 1.64 mL, 2.13 mmol) is added at −40° C. and the mixtureis stirred for 30 minutes. The crude mixture is kept at −40° C. anddirectly used for the next step.

Final Step (Example 1)

To (5-methoxypyridin-2-yl)magnesium chloride 1.1 (350 mg, 2.08 mmol) at−40° C. is added copper(I)cyanide di(lithium chloride) complex (1 mol/Lin tetrahydrofuran, 0.18 mL, 0.18 mmol) and the reaction mixture isstirred for 5 minutes at −40° C.6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C (110mg, 0.44 mmol) in 1.0 mL of tetrahydrofuran is slowly added and themixture is stirred at −40° C. When complete conversion is observed byHPLC-MS, the reaction mixture is diluted with methanol, concentratedunder reduced pressure and purified by RP-HPLC (modifier: ammoniumhydroxide)

Yield: 38 mg (32% of theory)

Mass spectrometry (ESI⁺): m/z=272 [M+H]⁺

HPLC (Method 1): Retention time=0.80 min.

Example 22-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-5-trifluoromethyl-isonicotinonitrile

2.2 4-cyano-5-(trifluoromethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1, obtained by starting from2-iodo-5-(trifuoromethyl)pyridine-4-carbonitrile 2.1 andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−62° C.

Final Step (Example 2)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C with[4-cyano-5-(trifluoromethyl)-2-pyridyl]magnesium chloride 2.2 at −65° C.When complete conversion is observed by HPLC-MS, the reaction mixture isquenched with methanol. The reaction mixture is concentrated underreduced pressure and the residue is partitioned between dichloromethaneand water. The organic phase is dried over magnesium sulfate andconcentrated. The residue is purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 4% of theory

Mass spectrometry (ESI⁺): m/z=335 [M+H]⁺

HPLC (Method 1): Retention time=0.87 min.

Example 36-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

3.1 (6-chloro-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-chloro-6-iodo-pyridine (from Anichem) and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution in tetrahydrofuran) at −45° C.

Final Step (Example 3)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C with(6-chloro-2-pyridyl)-magnesium chloride 3.1 at −45° C. When completeconversion is observed by HPLC-MS the reaction mixture is diluted withmethanol, concentrated under reduced pressure and purified by RP-HPLC(modifier: ammonium hydroxide)

Yield: 33% of theory

Mass spectrometry (ESI⁺): m/z=276 [M+H]⁺

HPLC (Method 1): Retention time=0.86 min.

Example 46-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-nicotinonitrile

4.2 (5-cyano-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from6-Iodo-nicotinonitrile 4.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 4)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-cyano-2-pyridyl)-magnesium chloride 4.2 at −65° C. When completeconversion is observed by HPLC-MS the reaction mixture is partitionedbetween with ethyl acetate and a half saturated aqueous solution ofsodium bicarbonate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The combined organic phase are dried,concentrated and purified by silica gel chromatography (eluent:cyclohexane/ethyl acetate 0%→65%). The product is recrystallized fromethyl acetate.

Yield: 20% of theory

Mass spectrometry (ESI⁺): m/z=267 [M+H]⁺

HPLC (Method 1): Retention time=0.73 min.

Example 56-(5-Bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

5.1 (5-bromo-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-Bromo-2-iodopyridine (from ABCR) and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 5)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-bromo-2-pyridyl)-magnesium chloride 5.1 at −65° C. When completeconversion is observed by HPLC-MS the reaction mixture is partitionedbetween with ethyl acetate and a half saturated aqueous solution ofsodium bicarbonate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The organic phase is dried, concentratedand purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 54% of theory

Mass spectrometry (ESI⁺): m/z=320, 322 [M+H]⁺

HPLC (Method 1): Retention time=0.84 min.

Example 65-Methyl-6-(5-trifluoromethyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

6.2 [5-(trifluoromethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-Iodo-5-trifluoromethyl-pyridine 6.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 6)

Obtained analogously to example 1 by starting from6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine C and[5-(trifluoromethyl)-2-pyridyl]-magnesium chloride 6.2. When completeconversion is observed by HPLC-MS the reaction mixture is partitionedbetween with ethyl acetate and a half saturated aqueous solution ofsodium bicarbonate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The organic phase is dried, concentratedand purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 49% of theory

Mass spectrometry (ESI⁺): m/z=310 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

Example 76-(6-Bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

7.1 (6-bromo-2-pyridyl)-magnesium Chloride

Analogously to example 1.1, obtained by starting from2,6-Dibromo-pyridine (from Aldrich) and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 7)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (6-bromo-2-pyridyl)-magnesium chloride 7.1 at −25° C. When completeconversion is observed by HPLC-MS the reaction mixture is partitionedbetween with ethyl acetate and a half saturated aqueous solution ofsodium bicarbonate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The organic phase is dried, concentratedand purified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 49% of theory

Mass spectrometry (ESI⁺): m/z=320, 322 [M+H]⁺

HPLC (Method 3): Retention time=0.87 min.

Example 86-(5-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

8.1 (5-chloro-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-Chloro-2-iodo-pyridine (from Activate) and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 8)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C with(5-chloro-2-pyridyl)-magnesium chloride 8.1 at −25° C. When completeconversion is observed by HPLC-MS the reaction mixture is partitionedbetween with ethyl acetate and a half saturated aqueous solution ofsodium bicarbonate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The organic phase is dried, concentratedand purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 59% of theory

Mass spectrometry (ESI⁺): m/z=276 [M+H]⁺

HPLC (Method 1): Retention time=0.62 min.

Example 96-(5-Difluoromethyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

9.2 [5-(difluoromethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-Difluoromethyl-2-iodo-pyridine 9.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 9)

Obtained analogously to example 1 by reacing6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [5-(difluoromethyl)-2-pyridyl]-magnesium chloride 9.2 at −25° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 40% of theory

Mass spectrometry (ESI⁺): m/z=292 [M+H]⁺

HPLC (Method 1): Retention time=0.78 min.

Example 10[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridin-3-yl]-aceticAcid Methyl Ester

10.3 [5-(2-methoxy-2-oxo-ethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1, obtained by starting from(6-Iodo-pyridin-3-yl)acetic acid methyl ester 10.2 andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−60° C.

Final Step (Example 10)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [5-(2-methoxy-2-oxo-ethyl)-2-pyridyl]magnesium chloride 10.3. at−25° C. When complete conversion is observed by HPLC-MS the reactionmixture is partitioned between with ethyl acetate and a half saturatedaqueous solution of sodium bicarbonate. The phases are separated and theaqueous phase is extracted with ethyl acetate. The organic phase isdried, concentrated and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 28% of theory

Mass spectrometry (ESI⁺): m/z=314 [M+H]⁺

HPLC (Method 1): Retention time=0.76 min.

Example 116-[5-(1,1-Difluoro-ethyl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

11.2 [5-(1,1-difluoroethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1, obtained by starting from5-(1,1-difluoro-ethyl)-2-iodo-pyridine 11.1 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 11)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C with[5-(1,1-difluoroethyl)-2-pyridyl]-magnesium chloride 11.2 at −25° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 44% of theory

Mass spectrometry (ESI⁺): m/z=306 [M+H]⁺

HPLC (Method 1): Retention time=0.85 min.

Example 126-(5-Fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

12.2 (5-fluoro-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-Fluoro-2-iodo-pyridine 12.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 12)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-fluoro-2-pyridyl)-magnesium chloride 12.2 at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture isdiluted with methanol, concentrated under reduced pressure and purifiedby RP-HPLC (modifier: ammonium hydroxide).

Yield: 19% of theory

Mass spectrometry (ESI⁺): m/z=260 [M+H]⁺

HPLC (Method 1): Retention time=0.76 min.

Example 136-(6-Fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

13.2 (6-fluoro-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-Fluoro-6-iodo-pyridine 13.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 13)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (6-fluoro-2-pyridyl)-magnesium chloride 13.2. at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture isdiluted with methanol, concentrated under reduced pressure and purifiedby RP-HPLC (modifier: ammonium hydroxide).

Yield: 8% of theory

Mass spectrometry (ESI⁺): m/z=260 [M+H]⁺

HPLC (Method 1): Retention time=0.78 min.

Example 146-(5-Difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

14.3 [5-(difluoromethoxy)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-Difluoromethoxy-2-iodo-pyridine 14.2 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −45° C.

Final Step (Example 14)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [5-(difluoromethoxy)-2-pyridyl]-magnesium chloride 14.3 at −65° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 7% of theory

Mass spectrometry (ESI⁺): m/z=308 [M+H]⁺

HPLC (Method 2): Retention time=0.76 min.

Example 156-(6-Bromo-5-difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

15.3 [6-bromo-5-(difluoromethoxy)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-Bromo-3-difluoromethoxy-6-iodo-pyridine 15.2 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 15)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C with[6-bromo-5-(difluoromethoxy)-2-pyridyl]-magnesium chloride 15.3 at −65°C. When complete conversion is observed by HPLC-MS the reaction mixtureis partitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 74% of theory

Mass spectrometry (ESI⁺): m/z=386, 388 [M+H]⁺

HPLC (Method 1): Retention time=0.91 min.

Example 165-Methyl-6-(6-methylsulfanyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

16.2 (6-methylsulfanyl-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-iodo-6-methylsulfanyl-pyridine 16.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 16)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (6-methylsulfanyl-2-pyridyl)-magnesium chloride 16.2 at −65° C.When complete conversion is observed by HPLC-MS the reaction mixture isdiluted with methanol, concentrated under reduced pressure and purifiedby silica gel chromatography (eluent: cyclohexane/ethyl acetate100/0→20/80).

Yield: 29% of theory

Mass spectrometry (ESI⁺): m/z=288 [M+H]⁺

HPLC (Method 3): Retention time=0.90 min.

Example 175-Methyl-6-(5-trifluoromethoxy-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

17.1 [5-(trifluoromethoxy)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1, obtained by starting from5-Difluoromethoxy-2-iodo-pyridine (from GainBiotech) andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−55° C.

Final Step (Example 17)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C with[5-(trifluoromethoxy)-2-pyridyl]-magnesium chloride 17.1 at −65° C. Whencomplete conversion is observed by HPLC-MS, the reaction mixture isdiluted with methanol. The reaction mixture is concentrated underreduced pressure and the residue is partitioned between dichloromethaneand water. The organic phase is dried over magnesium sulfate andconcentrated. The residue is purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 26% of theory

Mass spectrometry (ESI⁺): m/z=326 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 186-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

18.1 (2,3-dihydro-)[1,4]dioxino[2,3-b]pyridine-6-yl)-magnesium Chloride

Analogously to example 1.1, obtained by starting from6-iodo-2,3dihydro-[1,4]dioxino[2,3-b]pyridine (from Adesis) andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−50° C.

Final Step (Example 18)

Obtained analogously to example 1 by starting from6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C and(2,3-dihydro-)[1,4]dioxino[2,3-b]pyridine-6-yl)-magnesium chloride 18.1.When complete conversion is observed by HPLC-MS, the reaction mixtureconcentrated under reduced pressure and the residue is purified bysilica gel chromatography (eluent: petroleum ether/ethyl acetate38/62→0/100). The residue is dissolved in methanol, concentrated underreduced pressure and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 30% of theory

Mass spectrometry (ESI⁺): m/z=300 [M+H]⁺

HPLC (Method 10): Retention time=0.63 min.

Example 196-(5-Brom32.2-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

19.3 (5-bromo-6-chloro-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from3-bromo-2-chloro-6-iodo-pyridine 19.2 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 19)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-bromo-6-chloro-2-pyridyl)-magnesium chloride 19.3 at −55° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 10% of theory

Mass spectrometry (ESI⁺): m/z=354, 356 [M+H]⁺

HPLC (Method 4): Retention time=0.90 min.

Example 206-(4-Chloro-5-trifluoromethyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

20.2 [4-chloro-5-(trifluoromethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from4-chloro-2-iodo-5-trifluoromethyl-pyridine 20.1 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −55° C.

Final Step (Example 20)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [4-chloro-5-(trifluoromethyl)-2-pyridyl]-magnesium chloride 20.2 at−55° C. When complete conversion is observed by HPLC-MS the reactionmixture is diluted with methanol, concentrated under reduced pressureand purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 24% of theory

Mass spectrometry (ESI⁺): m/z=344 [M+H]⁺

HPLC (Method 1): Retention time=0.95 min.

Example 216-(5,6-Dibromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

21.3 (5,6-dibromo-2-pyridyl)-magnesium Chloride

Analogously to example 1.1, obtained by starting from2,3-dibromo-6-iodo-pyridine 21.2 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 21)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5,6-dibromo-2-pyridyl)-magnesium chloride 21.3 at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by silica gel chromatography (eluent:cyclohexane/ethyl acetate 100/0->50/50).

Yield: 8% of theory

Mass spectrometry (ESI⁺): m/z=397, 399, 401 [M+H]⁺

HPLC (Method 4): Retention time=0.91 min.

Example 226-(5-Brom32.2-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

22.3 (5-bromo-6-fluoro-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from3-bromo-2-fluoro-6-iodo-pyridine 22.2 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 22)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-bromo-6-fluoro-2-pyridyl)-magnesium chloride 22.3 at −70° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by silica gel chromatography (eluent:cyclohexane/ethyl acetate 100/0->50/50).

Yield: 69% of theory

Mass spectrometry (ESI⁺): m/z=338, 340 [M+H]⁺

HPLC (Method 4): Retention time=0.84 min.

Example 236-(5-Brom32.2-difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

23.4 [5-bromo-6-(difluoromethoxy)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from3-bromo-2-difluoromethoxy-6-iodo-pyridine 23.3 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 23)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [5-bromo-6-(difluoromethoxy)-2-pyridyl]-magnesium chloride 23.4 at−65° C. When complete conversion is observed by HPLC-MS the reactionmixture is partitioned between with ethyl acetate and a half saturatedaqueous solution of sodium bicarbonate. The phases are separated and theaqueous phase is extracted with ethyl acetate. The organic phase isdried, concentrated and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 76% of theory

Mass spectrometry (ESI⁺): m/z=386, 388 [M+H]⁺

HPLC (Method 1): Retention time=0.97 min.

Example 246-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile

24.4 (6-chloro-5-cyano-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-Chloro-6-iodo-nicotinonitrile 24.3 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 24)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (6-chloro-5-cyano-2-pyridyl)-magnesium chloride 24.4 at −70° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by silica gel chromatography (eluent:cyclohexane/ethyl acetate 100/0->50/50).

Yield: 84% of theory

Mass spectrometry (ESI⁺): m/z=301 [M+H]⁺

HPLC (Method 4): Retention time=0.79 min.

Example 256-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile

25.4 (6-cyano-5-fluoro-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from3-Fluoro-6-iodo-pyridine-2-carbonitrile 25.3 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 25)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (6-cyano-5-fluoro-2-pyridyl)-magnesium chloride 25.4 at −65° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by silica gel chromatography (eluent:cyclohexane/ethyl acetate 100/0->50/50).

Yield: 75% of theory

Mass spectrometry (ESI⁺): m/z=285 [M+H]⁺

HPLC (Method 1): Retention time=0.83 min.

Example 265-Methyl-6-(4-trifluoromethyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

26.2 [4-(trifluoromethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-iodo-4-trifluoromethyl-pyridine 26.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −55° C.

Final Step (Example 26)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [4-(trifluoromethyl)-2-pyridyl]-magnesium chloride 26.2. at −65° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 50% of theory

Mass spectrometry (ESI⁺): m/z=310 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 272-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-5-bromo-isonicotinonitrile

27.2 (5-bromo-4-cyano-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-bromo-2-iodo-isonicotinonitrile 27.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 27)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-bromo-4-cyano-2-pyridyl)-magnesium chloride 27.2 at −60° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture isdiluted with methanol, concentrated under reduced pressure and purifiedby RP-HPLC (modifier: ammonium hydroxide).

Yield: 4% of theory

Mass spectrometry (ESI⁺): m/z=344, 346 [M+H]⁺

HPLC (Method 1): Retention time=0.84 min.

Example 282-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-isonicotinonitrile

28.2 (4-cyano-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-iodo-isonicotinonitrile 28.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 28)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (4-cyano-2-pyridyl)-magnesium chloride 28.2 at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 46 mg (34% of theory)

Mass spectrometry (ESI⁺): m/z=267 [M+H]⁺

HPLC (Method 1): Retention time=0.74 min.

Example 292-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-isonicotinamide

29.3 (4-carbamoyl-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-iodo-isonicotinamide 29.2 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 29)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (4-carbamoyl-2-pyridyl)-magnesium chloride 29.3 at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 48% of theory

Mass spectrometry (ESI⁺): m/z=285 [M+H]⁺

HPLC (Method 1): Retention time=0.62 min.

Example 306-(5-Chloro-pyrimidin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

30.1 (5-chloropyrimidin-2-yl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-chloro-2-iodo-pyrimidine (from Activate) and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 30)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-chloropyrimidin-2-yl)-magnesium chloride 30.1 at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 32% of theory

Mass spectrometry (ESI⁺): m/z=277 [M+H]⁺

HPLC (Method 1): Retention time=0.79 min.

Example 316-(5-Bromo-pyrimidin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

31.1 (5-bromopyrimidin-2-yl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-bromo-2-iodo-pyrimidine (from Aldrich) and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −45° C.

Final Step (Example 31)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith (5-bromopyrimidin-2-yl)-magnesium chloride 31.1 at −65° C.

When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 0.03 g (14% of theory)

Mass spectrometry (ESI⁺): m/z=320, 322 [M+H]⁺

HPLC (Method 1): Retention time=0.82 min.

Example 326-(5-Bromo-4-trifluoromethyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

32.3 [5-bromo-4-(trifluoromethyl)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from5-Bromo-2-iodo-4-trifluoromethyl-pyridine 32.2 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 32)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [5-bromo-4-(trifluoromethyl)-2-pyridyl]-magnesium chloride 32.3 at−65° C. When complete conversion is observed by HPLC-MS the reactionmixture is partitioned between with ethyl acetate and a half saturatedaqueous solution of sodium bicarbonate. The phases are separated and theaqueous phase is extracted with ethyl acetate. The organic phase isdried, concentrated and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 23% of theory

Mass spectrometry (ESI⁺): m/z=387, 389 [M+H]⁺

HPLC (Method 1): Retention time=0.98 min.

Example 336-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-trifluoromethoxy-pyridine-2-carbonitrile

33.4 [6-cyano-5-(trifluoromethoxy)-2-pyridyl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from6-Iodo-3-trifluoromethoxy-pyridine-2-carbonitrile 33.3 andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−70° C.

Final Step (Example 33)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine C with[6-cyano-5-(trifluoromethoxy)-2-pyridyl]-magnesium chloride 33.4. at−70° C. When complete conversion is observed by HPLC-MS the reactionmixture is diluted with methanol, concentrated under reduced pressureand purified by silica gel chromatography (eluent: cyclohexane/ethylacetate 0%→40%).

Yield: 62% of theory

Mass spectrometry (ESI⁺): m/z=351 [M+H]⁺

HPLC (Method 1): Retention time=0.91 min.

Example 345-Methyl-6-(4-trifluoromethyl-pyrimidin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

34.2 [4-(trifluoromethyl)pyrimidin-2-yl]-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-Iodo-4-trifluoromethyl-pyrimidine 34.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −55° C.

Final Step (Example 34)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith [4-(trifluoromethyl)pyrimidin-2-yl]-magnesium chloride 34.2 at −70°C. When complete conversion is observed by HPLC-MS the reaction mixtureis partitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by silica gel chromatography (eluent:cyclohexane/ethyl acetate 0%→50%).

Yield: 35% of theory

Mass spectrometry (ESI⁺): m/z=311 [M+H]⁺

HPLC (Method 1): Retention time=0.81 min.

Example 355-methyl-6-[5-(trifluoromethyl)pyrimidin-2-yl]methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

35.2 2-(chloromagnesio)-5-(trifluoromethyl)pyrimidine

Analogously to example 1.1, obtained by starting from2-iodo-5-(trifluoromethyl)pyrimidine 35.1 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −65° C.

Final Step (Example 35)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith 2-(chloromagnesio)-5-(trifluoromethyl)pyrimidine 35.2 at −70° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by chromatography on silica gel (using asolvent gradient from cyclohexane/ethyl acetate 100/0 to 50/50).

Yield: 9% of theory

Mass spectrometry (ESI⁺): m/z=311 [M+H]⁺

HPLC (Method 1): Retention time=0.83 min.

Example 366-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-(trifluoromethyl)pyridine-2-carbonitrile

36.2 6-(chloromagnesio)-4-(trifluoromethyl)pyridine-2-carbonitrile

Analogously to example 1.1, obtained by starting from6-iodo-4-(trifluoromethyl)pyridine-2-carbonitrile 36.1 andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−70° C.

Final Step (Example 36)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith 6-(chloromagnesio)-4-(trifluoromethyl)pyridine-2-carbonitrile 36.2at −70° C. When complete conversion is observed by HPLC-MS the reactionmixture is partitioned between with ethyl acetate and a half saturatedaqueous solution of sodium bicarbonate. The phases are separated and theaqueous phase is extracted with ethyl acetate. The organic phase isdried, concentrated and purified by chromatography on silica gel (usinga solvent gradient from cyclohexane/ethyl acetate 100/0 to 50/50).

Yield: 48% of theory

Mass spectrometry (ESI⁺): m/z=335 [M+H]⁺

HPLC (Method 1): Retention time=0.90 min.

Example 376-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-(trifluoromethyl)pyridine-2-carbonitrile

37.4 6-(chloromagnesio)-3-(difluoromethyl)pyridine-2-carbonitrile

Analogously to example 1.1 obtained by starting from3-(difluoromethyl)-6-iodopyridine-2-carbonitrile 37.3 andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−70° C.

Final Step (Example 37)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine C and6-(chloromagnesio)-3-(difluoromethyl)pyridine-2-carbonitrile 37.4 at−65° C. When complete conversion is observed by HPLC-MS the reactionmixture is partitioned between with ethyl acetate and a half saturatedaqueous solution of sodium bicarbonate. The phases are separated and theaqueous phase is extracted with ethyl acetate. The organic phase isdried, concentrated and purified by chromatography on silica gel (usinga solvent gradient from cyclohexane/ethyl acetate 100/0 to 50/50).

Yield: 32% of theory

Mass spectrometry (ESI⁺): m/z=317 [M+H]⁺

HPLC (Method 1): Retention time=0.86 min.

Example 386-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-chloropyridine-2-carbonitrile

38.2 4-chloro-6-(chloromagnesio)pyridine-2-carbonitrile

Analogously to example 1.1 obtained by starting from4-chloro-6-iodopyridine-2-carbonitrile 38.1 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 38)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith 4-chloro-6-(chloromagnesio)pyridine-2-carbonitrile 38.2 at −70° C.When complete conversion is observed by HPLC-MS the reaction mixture isdiluted with methanol, concentrated under reduced pressure and purifiedby chromatography on silica gel (using a solvent gradient fromcyclohexane/ethyl acetate 100/0 to 50/50).

Yield: 26% of theory

Mass spectrometry (ESI⁺): m/z=301 [M+H]⁺

HPLC (Method 1): Retention time=0.84 min.

Example 396-[(5-cyclopropylpyridin-2-yl)methyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

39.2 2-(chloromagnesio)-5-cyclopropylpyridine

Analogously to example 1.1 obtained by starting from5-cyclopropyl-2-iodopyridine 39.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 39)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine C and2-(chloromagnesio)-5-cyclopropylpyridine 39.2 at −65° C.

When complete conversion is observed by HPLC-MS the reaction mixture isdiluted with methanol, concentrated under reduced pressure and purifiedby RP-HPLC (modifier: ammonium hydroxide).

Yield: 18% of theory

Mass spectrometry (ESI⁺): m/z=282 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 406-[(5-cyclopropylpyridin-2-yl)methyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

40.3 2-(chloromagnesio)-5-cyclopropylpyridine-4-carbonitrile

Analogously to example 1.1 obtained by starting from5-cyclopropyl-2-iodopyridine-4-carbonitrile 40.2 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 40)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith 2-(chloromagnesio)-5-cyclopropylpyridine-4-carbonitrile 40.3 at−65° C. When complete conversion is observed by HPLC-MS the reactionmixture is diluted with methanol, concentrated under reduced pressureand purified by RP-HPLC (modifier: ammonium hydroxide). The residue ispurified by flash column chromatography on silica gel (using a solventgradient from dichloromethane/methanol 99/1 to 86/14).

Yield: 5% of theory

Mass spectrometry (ESI⁺): m/z=307 [M+H]⁺

HPLC (Method 2): Retention time=0.76 min.

Example 416-[(5-cyclopropoxypyridin-2-yl)methyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

41.3 2-(chloromagnesio)-5-cyclopropoxypyridine

Analogously to example 1.1 obtained by starting from5-cyclopropoxy-2-iodopyridine 41.2 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 41)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith 2-(chloromagnesio)-5-cyclopropoxypyridine 41.3 at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by chromatography on silica gel (using asolvent gradient from petrolether/ethyl acetate 88/12 to 0/100).

Yield: 3% of theory

Mass spectrometry (ESI⁺): m/z=298 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

Example 42 6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-cyclopropylpyridine-2-carbonitrile

42.3 6-(chloromagnesio)-3-cyclopropylpyridine-2-carbonitrile

Analogously to example 1.1 obtained by starting from3-cyclopropyl-6-iodopyridine-2-carbonitrile 42.2 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 42)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine C and6-(chloromagnesio)-3-cyclopropylpyridine-2-carbonitrile 42.3 at −75° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by chromatography on silica gel (using asolvent gradient from dichloromethane/methanol 88/12 to 0/100).

Yield: 38% of theory

Mass spectrometry (ESI⁺): m/z=307 [M+H]⁺

HPLC (Method 1): Retention time=0.90 min.

Example 436-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-cyclopropylpyridine-3-carbonitrile

43.4 6-(chloromagnesio)-2-cyclopropylpyridine-3-carbonitrile

Analogously to example 1.1 obtained by starting from2-cyclopropyl-6-iodopyridine-3-carbonitrile 43.3 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 43)

Obtained analogously to example 1 by reacting6-(bromomethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-aminehydrobromide D with6-(chloromagnesio)-2-cyclopropylpyridine-3-carbonitrile 43.4 at −65° C.When complete conversion is observed by HPLC-MS the reaction mixture ispartitioned between with ethyl acetate and a half saturated aqueoussolution of sodium bicarbonate. The phases are separated and the aqueousphase is extracted with ethyl acetate. The organic phase is dried,concentrated and purified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 9% of theory

Mass spectrometry (ESI⁺): m/z=307 [M+H]⁺

HPLC (Method 2): Retention time=0.81 min.

Example 445-Methyl-6-(5-methylsulfanyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

44.2 (5-methylsulfanyl-2-pyridyl)-magnesium Chloride

Analogously to example 1.1 obtained by starting from2-iodo-5-methylsulfanyl-pyridine 44.1 and isopropylmagnesium chloridelithiumchloride complex (1.3 M solution) at −60° C.

Final Step (Example 44)

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine C and(5-methylsulfanyl-2-pyridyl)-magnesium chloride 44.2 at −65° C. Whencomplete conversion is observed by HPLC-MS the reaction mixture isdiluted with methanol, concentrated under reduced pressure and purifiedby silica gel chromatography (eluent: cyclohexane/ethyl acetate 0%→80%).

Yield: 11% of theory

Mass spectrometry (ESI⁺): m/z=288 [M+H]⁺

HPLC (Method 3): Retention time=0.80 min.

Example 454-amino-2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-5-carbonitrile

45.3(E)-N′-[2-(chloromagnesio)-5-cyanopyrimidin-4-yl]-N,N-dimethylmethanimidamide

Analogously to example 1.1, obtained by starting from(E)-N′-(5-cyano-2-iodopyrimidin-4-yl)-N,N-dimethylmethanimidamide 45.2and isopropylmagnesium chloride lithiumchloride complex (1.3 M solution)at −70° C.

45.4(E)-N′-[2-({7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-yl}methyl)-5-cyanopyrimidin-4-yl]-N,N-dimethylmethanimidamide

Obtained analogously to example 1 by reacting6-chloromethyl-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-ylamine Cwith(E)-N′-[2-(chloromagnesio)-5-cyanopyrimidin-4-yl]-N,N-dimethylmethanimidamide45.3 at −65° C. When complete conversion is observed by HPLC-MS thereaction mixture is diluted with methanol, concentrated under reducedpressure and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 13% of theory

Mass spectrometry (ESI⁺): m/z=338 [M+H]⁺

HPLC (Method 1): Retention time=0.81 min.

Final Step (Example 45)

(E)-N′-[2-({7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-yl}methyl)-5-cyanopyrimidin-4-yl]-N,N-dimethylmethanimidamide45.4 (20.0 mg, 0.06 mmol) and 0.2 mL HCl (32% aqueous solution) aredissolved in 2.0 mL methanol and the mixture is stirred for 10 minutes.The mixture is purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 5.9 mg (35% of theory)

Mass spectrometry (ESI⁺): m/z=283 [M+H]⁺

Example 462-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-5-(trifluoromethyl)pyrimidin-4-amine

Solution #1: 2-iodo-5-(trifluoromethyl)pyrimidin-4-amine 46.3 (2.00 g,6.93 mmol) is dissolved in 30 mL of tetrahydrofuran and the mixture iscooled to −60° C. Isopropylmagnesium chloride lithium complex (1.3 Msolution, 11.15 mL, 14.49 mmol) is added dropwise and the mixture isstirred for 20 minutes.

Solution #2: 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethylacetate E (1.40 g, 6.30 mmol) is dissolved in 20 mL of tetrahydrofuranand cooled to −70° C. Copper cyanide lithium chloride complex (1 Msolution, 6.62 mL, 6.62 mmol) is added.

Under argon atmosphere solution #1 containing 46.4 is slowly added viacannula to solution #2 keeping the internal temperature below −60° C.Lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 6.30mL, 6.30 mmol) is slowly added at −60° C. and the mixture is warmed to−30° C. The mixture is acidified with 4 M hydrochloric acid, poured intosaturated aqueous ammonium chloride/ammonia (9/1 v/v solution) andextracted with ethyl acetate. The combined organic phases are dried andconcentrated under reduced pressure. The residue is purified bychromatography on silica gel (using a solvent gradient cyclohexane/ethylacetate from 100/0 to 40/60).

Yield: 736 mg (36% of theory)

Mass spectrometry (ESI⁺): m/z=326 [M+H]⁺

HPLC (Method 1): Retention time=0.80 min.

Example 476-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-chloropyridine-2-carbonitrile

47.2 3-chloro-6-(chloromagnesio)pyridine-2-carbonitrile

Analogously to example 46 obtained by starting from3-chloro-6-iodopyridine-2-carbonitrile 47.1 and isopropylmagnesiumchloride lithiumchloride complex (1.3 M solution) at −70° C.

Final Step (Example 47)

Analogously to example 46, obtained by starting from3-chloro-6-(chloromagnesio)pyridine-2-carbonitrile 47.2 and7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl acetate E.The mixture is purified by flash column chromatography on silica gel(using a solvent gradient cyclohexane/ethyl acetate from 100/0 to20/80).

Yield: 49% of theory

Mass spectrometry (ESI⁺): m/z=301 [M+H]⁺

HPLC (Method 1): Retention time=0.85 min.

Example 486-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-trifluoromethyl-pyridine-2-carbonitrile

48.4 6-(chloromagnesio)-3-(trifluoromethyl)pyridine-2-carbonitrile

Analogously to example 46 obtained by starting from6-Iodo-(3-trifluoromethyl)pyridine-2-carbonitrile 48.3 andisopropylmagnesium chloride lithiumchloride complex (1.3 M solution) at−70° C.

Final Step (Example 48)

Analogously to example 46 obtained by starting from6-(chloromagnesio)-3-(trifluoromethyl)-pyridine-2-carbonitrile 48.4 and7-amino-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-6-ylmethyl acetate E.The mixture is purified by flash column chromatography on silica gel(using a solvent gradient from cyclohexane/ethyl acetate 100/0 to20/80).

Yield: 73% of theory

Mass spectrometry (ESI⁺): m/z=335 [M+H]⁺

HPLC (Method 1): Retention time=0.91 min.

Example 491-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-trifluoromethyl-pyridin-2-yl]-2-methyl-propan-1-one

Analogously to example 48 obtained aside from example 48 when 1.5equivalents of Grignard reagent are used and lithiumbis(trimethylsilyl)amide is not added to the reaction mixture. Themixture is purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 20% of theory

Mass spectrometry (ESI⁺): m/z=380 [M+H]⁺

HPLC (Method 1): Retention time=0.93 min.

Example 506-[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

Analogously to example 46, obtained by starting from4-chloro-2-iodo-5-(trifluoromethyl)pyrimidine 50.1 and7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl acetate E.The mixture is purified by RP-HPLC (modifier: ammonium hydroxide)

Yield: 6% of theory

Mass spectrometry (ESI⁺): m/z=345 [M+H]⁺

HPLC (Method 1): Retention time=0.94 min.

Example 512-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-4-carbonitrile

Analogously to example 46, obtained by starting from2-iodopyrimidine-4-carbonitrile 51.1 and7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl acetate E.The mixture is purified by flash column chromatography on silica gel(using a solvent gradient from cyclohexane/ethyl acetate 100/0 to20/80).

Yield: 10% of theory

Mass spectrometry (ESI⁺): m/z=268 [M+H]⁺

HPLC (Method 1): Retention time=0.73 min.

Example 525-Methyl-6-(6-trifluoromethyl-pyridin-2-ylmethyl)[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

52.1 4-(6-Trifluoromethyl-pyridin-2-yl)-butan-2-one

A mixture of commercially available (Frontier)2-(chloromethyl)-6-(trifluoromethyl)pyridine (1.00 g, 5.11 mmol), acetylacetone (0.53 mL, 5.11 mmol) and potassium carbonate (710 mg, 5.11 mmol)in 25 mL methanol is stirred at 80° C. for 18 hours. Water is added andthe product is extracted with dichloromethane. The organic layer isdried and concentrated under reduced pressure. The residue is purifiedby silica gel chromatography (eluent: petrol ether/ethyl acetate100/0->85/15)

Mass spectrometry (ESI⁺): m/z=192 [M+H]⁺

HPLC (Method 3): Retention time=0.94 min.

Final Step (Example 52)

Under nitrogen atmosphere commercially available4-amino-1,2,5-oxadiazole-3-carbonitrile (ABCR) (45.0 mg, 0.41 mmol) and4-(6-trifluoromethyl-pyridin-2-yl)-butan-2-one 52.1 (88.79 mg, 0.41mmol) are dissolved in 2.0 mL of toluene. Tin(IV)chloride (0.10 mL, 0.82mmol) is added and the mixture is stirred at room temperature for 30minutes. The mixture is stirred at 110° C. for 18 hours. The solid isfiltered and purified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 6 mg (5% of theory)

Mass spectrometry (ESI⁺): m/z=310 [M+H]⁺

HPLC (Method 2): Retention time=0.82 min.

Example 53 5-Methyl-6-(6-methyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

53.1 4-(6-Methyl-pyridin-2-yl)-butan-2-one

Analogously to intermediate 52.1, obtained by starting from commerciallyavailable (BroadPharma) 2-(chloromethyl)-6-(methyl)pyridine and acetylacetone. The mixture is purified by RP-HPLC (modifier: NH₄OH).

Mass spectrometry (ESI⁺): m/z=164 [M+H]⁺

HPLC (Method 1): Retention time=0.73 min.

Final Step (Example 53)

Analogously to Example 52, obtained by starting from commerciallyavailable 4-amino-1,2,5-oxadiazole-3-carbonitrile (ABCR) and4-(6-methyl-pyridin-2-yl)-butan-2-one 53.1. The mixture is stirred atreflux for 1 hour. The precipitate is collected via filtration andsuspended in 1 M sodium hydroxide solution. The suspension is extractedwith ethyl acetate. The organic phase is dried and concentrated underreduced pressure. The residue is purified by RP-HPLC (modifier: NH₄OH).

Yield: 4% of theory

Mass spectrometry (ESI⁺): m/z=256 [M+H]⁺

HPLC (Method 1): Retention time=0.82 min.

Example 546-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carboxylicacid methylamide

54.1 6-(3-Oxo-butyl)-pyridine-2-carboxylic Acid Methyl Ester

Analogously to intermediate 52.1 obtained by starting from commerciallyavailable (Activate) 6-bromomethylpyridine-2-carboxylic acid methylester and acetyl acetone.

Yield: 32% of theory

Mass spectrometry (ESI⁺): m/z=208 [M]⁺

HPLC (Method 3): Retention time=0.74 min.

54.26-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carboxylicAcid

Commercially available 4-Amino-1,2,5-oxadiazole-3-carbonitrile (ABCR)(303 mg, 2.76 mmol) and 6-(3-Oxobutyl)-pyridine-2-carboxylic acid methylester 54.1 (571 mg, 2.76 mmol) are dissolved in 20 mL of toluene.Tin(IV) chloride (0.65 mL, 5.51 mmol) is added and the mixture isstirred at room temperature for 30 minutes and then for 19 hours atreflux. The mixture is concentrated under reduced pressure and theresidue is taken up in methanol. An aqueous solution of sodium hydroxideis added and tin salts are filtered. The filtrate is purified by RP-HPLC(modifier: trifluoroacetic acid).

Yield: 170 mg (22% of theory)

Mass spectrometry (ESI⁺): m/z=286 [M+H]⁺

HPLC (Method 3): Retention time=0.61 min.

Final Step (Example 54)

6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carboxylicacid 54.2 (50.0 mg, 0.18 mmol),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (73.3 mg, 0.19 mmol) and N,N-diisopropylethylamine(70 μL, 0.39 mmol) in 0.5 mL N,N-dimethylformamide are stirred at roomtemperature for 15 minutes. Methyl amine (2 M solution intetrahydrofuran; 0.18 mL, 0.35 mmol) is added and the mixture is stirredat room temperature for 18 hours. The mixture is diluted with methanol,acidified with trifluoroacetic acid and purified by RP-HPLC (modifier:trifluoroacetic acid). The product is obtained after anotherpurification by RP-HPLC (modifier: ammonium hydroxide)

Yield: 21 mg (40% of theory)

Mass spectrometry (ESI⁺): m/z=299 [M+H]⁺

HPLC (Method 1): Retention time=0.73 min.

Example 556-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carboxylicAcid Dimethylamide

Obtained by starting from6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carboxylicacid 54.2 and dimethyl amine (2 M solution in tetrahydrofuran).

Yield: 5.5 mg (10% of theory)

Mass spectrometry (ESI⁺): m/z=313 [M+H]⁺

HPLC (Method 1): Retention time=0.72 min.

Final Step (Example 56)6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carboxylicAcid Amide

6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carboxylicacid 54.2 (320 mg, 1.1 mmol) is taken in 5 mL N,N-dimethylformamide andN,N′-carbonyldiimidazole (190 mg, 1.2 mmol). The mixture is stirred for2 hours at room temperature. The mixture is cooled to 0° C. beforeammonia (32% aqueous solution, 1.9 mL) is added. The mixture is stirredfor 18 hours at room temperature. The mixture is purified by RP-HPLC(modifier: ammonium hydroxide).

Yield: 130 mg (41% of theory)

Mass spectrometry (ESI⁺): m/z=285 [M+H]⁺

HPLC (Method 3): Retention time=0.63 min.

Example 576-(6-Furan-2-yl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

6-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 3) (50.0 mg, 0.18 mmol), 2-Furanboronic acid (30.4 mg, 0.27mmol), potassium carbonate (2 M aqueous solution, 200 μL, 0.40 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (35.5 mg,54.4 μmol) are dissolved in 2.0 mL dioxane. The mixture is stirred at100° C. for 1 hour. The mixture is purified by RP-HPLC (modifier:ammonium hydroxide).

Yield: 8 mg (14% of theory)

Mass spectrometry (ESI⁺): m/z=308 [M+H]⁺

HPLC (Method 1): Retention time=0.92 min.

Example 585-methyl-6-[(pyridin-2-yl)methyl]-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

Obtained as a by-product when synthesizing Example 57. The mixture ispurified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 16 mg (37% of theory)

Mass spectrometry (ESI⁺): m/z=242 [M+H]⁺

HPLC (Method 1): Retention time=0.72 min.

Example 59 5-Methyl-6-[6-(3-methyl-3H-imidazol-4-yl)-pyridin-2-ylmethyl]-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 3) and (1-Methyl-1H-imidazol-5-yl)boronic acid pinacol ester.The mixture is purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 15 mg (25% of theory)

Mass spectrometry (ESI⁺): m/z=322 [M+H]⁺

HPLC (Method 1): Retention time=0.76 min.

Example 606-[6-(3,5-Dimethyl-isoxazol-4-yl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 3) and 3,5-Dimethyl-4-isoxazolboronic acid. The mixturefiltered over silica gel and purified by RP-HPLC (modifier:trifluoroacetic acid).

Yield: 28 mg (47% of theory)

Mass spectrometry (ESI⁺): m/z=337 [M+H]⁺

HPLC (Method 1): Retention time=0.87 min.

Example 615-Methyl-6-[6-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-pyridin-2-ylmethyl]-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 3) and 1-Methyl-3-trifluoromethylpyrazole-4-boronic acid. Themixture filtered and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 14 mg (39% of theory)

Mass spectrometry (ESI⁺): m/z=390 [M+H]⁺

HPLC (Method 3): Retention time=0.91 min.

Example 625-Methyl-6-[6-(3-trifluoromethyl-1H-pyrazol-4-yl)pyridin-2-ylmethyl]-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 3) and 3-(Trifluoromethyl)-1H-pyrazole-4-boronic acid pinacolester. The mixture is quenched with methanol, filtered and purified byRP-HPLC (modifier: ammonium hydroxide).

Yield: 61 mg (90% of theory)

Mass spectrometry (ESI⁺): m/z=376 [M+H]⁺

HPLC (Method 3): Retention time=0.86 min.

Example 632-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridin-2-yl]-2-methyl-propionitrile

6-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 3) (50.00 mg, 0.181 mmol), isobutyronitrile (0.100 mg, 1.447mmol) and sodium bis(trimethylsilyl)amide 1 M solution in THF (0.500 ml,0.50 mmol) are dissolved in 1.0 mL of tetrahydrofuran. The mixture isstirred at 100° C. for 15 minutes in a microwave. The mixture ispurified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 21 mg (37% of theory)

Mass spectrometry (ESI⁻): m/z=309 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

Example 641-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridin-2-yl]-cyclopentanecarbonitrile

Analogously to example 63, obtained by starting from6-(6-Chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 3) and cyclopentanecarbonitrile.

Yield: 34% of theory

Mass spectrometry (ESI⁻): m/z=335 [M+H]⁺

HPLC (Method 1): Retention time=0.93 min.

65.16-[5-Bromo-6-(2,4-dimethoxy-benzylamino)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(5-Bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 2,4-dimethoxy-benzylamine using diisopropylethylamineinstead of potassium fluoride. Stirred for 18 hours at 120° C. andpurified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 0.15 g (58% of theory)

Mass spectrometry (ESI⁺): m/z=484, 486 [M+H]⁺

HPLC (Method 4): Retention time=1.07 min.

65.26-(6-Amino-5-bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

To6-[5-Bromo-6-(2,4-dimethoxy-benzylamino)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]-oxadiazolo-[3,4-b]-pyridin-7-ylamine65.1 (0.271 g, 0.558 mmol) in 10 mL dichloromethane, is added 2.0 mLtrifluoroacetic acid. The mixture is stirred for 18 h, partitionedbetween saturated aqueous sodium bicarbonate solution anddichloromethane. The phases are separated and the aqueous phase isextracted with dichloromethane. The combined organic phase are dried andconcentrated under reduced pressure.

Yield: 0.20 g (107% of theory)

Mass spectrometry (ESI⁺): m/z=334, 336 [M+H]⁺

HPLC (Method 4): Retention time=0.83 min

Final Step (Example 65)6-[6-Amino-5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Amino-5-bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine65.2 and3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole.The mixture is filtered over silica gel und washed with ethyl acetate.The mixture is purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 15 mg (34% of theory)

Mass spectrometry (ESI⁺): m/z=363 [M+H]⁺

HPLC (Method 1): Retention time=0.81 min.

Example 666-[6-Amino-5-(3,5-dimethyl-isoxazol-4-yl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Amino-5-bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine65.2 and 3,5-dimethylisoxazole-4-boronic acid pinacol ester andadditional methanol. The mixture is filtered over silica gel und washedwith ethyl acetate. The mixture is purified by RP-HPLC (modifier:trifluoroacetic acid).

Yield: 18 mg (43% of theory)

Mass spectrometry (ESI⁺): m/z=352 [M+H]⁺

HPLC (Method 1): Retention time=0.91 min.

Example 676-(6-Amino-5-thiazol-5-yl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Amino-5-bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine65.2 and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole. Themixture is filtered over silica gel und washed with ethyl acetate. Themixture is purified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 12 mg (29% of theory)

Mass spectrometry (ESI⁺): m/z=340 [M+H]⁺

HPLC (Method 1): Retention time=0.63 min.

Example 686-[6-Amino-5-(2,4-dimethyl-2H-pyrazol-3-yl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Amino-5-bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine65.2 and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleand additional methanol. The mixture is filtered over silica gel andwashed with ethyl acetate. The organic phase is dried, concentratedunder reduced pressure and purified by RP-HPLC (modifier:trifluoroacetic acid). The residue is diluted in acetonitrile, basifiedwith triethylamine and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 8 mg (24% of theory)

Mass spectrometry (ESI⁺): m/z=351 [M+H]⁺

HPLC (Method 1): Retention time=0.82 min.

Example 696-(6-Amino-5-pyrazin-2-yl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained by starting from6-(6-Amino-5-bromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine65.2 and pyrazine-2-boronic acid pinacol ester and additional methanol.The mixture is diluted with methanol, filtered over silica gel. andpurified by RP-HPLC (modifier ammonium hydroxide).

Yield: 9 mg (22% of theory)

Mass spectrometry (ESI⁺): m/z=335 [M+H]⁺

HPLC (Method 1): Retention time=0.79 min.

Example 706-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-difluoromethoxy-pyridine-2-carbonitrile

6-(6-Bromo-5-difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 15) (45.0 mg, 0.12 mmol) is dissolved in 1.0 mL ofN,N-dimethylformamide. Bis(diphenylphosphino)ferrocene (6.48 mg, 0.01mmol) and zinc cyanide (14.9 mg, 0.13 mmol) are added and argon isbubbled through the reaction mixture for 10 minutes.(Tris(dibenzylideneacetone)dipalladium(0) (5.35 mg, 0.01 mmol) is addedand the reaction mixture is stirred at 120° C. for 10 minutes. Themixture is purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 25 mg (64% of theory)

Mass spectrometry (ESI⁺): m/z=333 [M+H]⁺

HPLC (Method 1): Retention time=0.86 min.

Example 716-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-bromopyridine-2-carbonitrile

Obtained analogously to example 70 by starting from6-(5,6-Dibromo-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 21) and zinc cyanide. The mixture is purified by RP-HPLC(modifier: ammonium hydroxide).

Yield: 30% of theory

Mass spectrometry (ESI⁺): m/z=345, 347 [M+H]⁺

HPLC (Method 4): Retention time=0.80 min.

Example 726-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile

Obtained analogously to example 70 by starting from6-(5-Bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and zinc cyanide. The mixture is purified by RP-HPLC(modifier: ammonium hydroxide).

Yield: 89% of theory

Mass spectrometry (ESI⁺): m/z=285 [M+H]⁺

HPLC (Method 4): Retention time=0.74 min.

Example 736-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-difluoromethoxy-nicotinonitrile

Obtained analogously to example 70 by starting from6-(5-Bromo-6-difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 23) and zinc cyanide. The mixture is purified by RP-HPLC(modifier: ammonium hydroxide).

Yield: 7% of theory

Mass spectrometry (ESI⁺): m/z=333 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 746-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-trifluoromethyl-nicotinonitrile

Obtained analogously to example 70 by starting from6-(5-Bromo-4-trifluoromethyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 32) and zinc cyanide. The mixture is purified by RP-HPLC(modifier: ammonium hydroxide).

Yield: 62% of theory

Mass spectrometry (ESI⁺): m/z=335 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 752-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-5-(trifluoromethyl)pyrimidine-4-carbonitrile

Obtained analogously to example 70 by starting from6-[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine(example 50) and zinc cyanide. The mixture is purified by RP-HPLC(modifier: ammonium hydroxide).

Yield: 23% of theory

Mass spectrometry (ESI⁺): m/z=336 [M+H]⁺

HPLC (Method 1): Retention time=0.87 min.

Example 766-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyridine-3,4-dicarbonitrile

Obtained analogously to example 70 by starting from2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-5-bromopyridine-4-carbonitrile(example 27) and zinc cyanide. The mixture is purified by RP-HPLC(modifier: ammonium hydroxide).

Yield: 76% of theory

Mass spectrometry (ESI⁺): m/z=292 [M+H]⁺

HPLC (Method 1): Retention time=0.78 min.

Example 772-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-5-carbonitrile

Obtained analogously to example 70 by starting from6-[(5-bromopyrimidin-2-yl)methyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine(example 31) and zinc cyanide. The reaction mixture is purified byRP-HPLC (modifier: ammonium hydroxide).

Yield: 87% of theory

Mass spectrometry (ESI⁺): m/z=268 [M+H]⁺

HPLC (Method 1): Retention time=0.71 min.

Example 782-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-(trifluoromethyl)pyrimidine-5-carbonitril

Obtained analogously to example 165 by starting from2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-5-carbonitrile(example 77) and zinc trifluoromethanesulfinate. The mixture is purifiedby RP-HPLC (modifier: ammonium hydroxide)

Yield: 13% of theory

Mass spectrometry (ESI⁺): m/z=336 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

Example 792-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-(difluoromethyl)pyrimidine-5-carbonitrile

Obtained analogously to example 165 by starting from2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-5-carbonitrile(example 77) and zinc difluoromethanesulfinate. The mixture is purifiedby RP-HPLC (modifier: ammonium hydroxide)

Yield: 12% of theory

Mass spectrometry (ESI⁺): m/z=318 [M+H]⁺

HPLC (Method 1): Retention time=0.81 min.

Example 802-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-(oxolan-3-yl)pyrimidine-5-carbonitrile

2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-5-carbonitrile(example 77) (25.0 mg, 0.09 mmol) is added to a mixture of 1.5 mLdiethylcarbonate and 1.0 mL water. Sodium oxolane-3-sulfinate (44.4 mg,0.28 mmol) is added and the mixture is cooled with an ice bath.2-methyl-prop-2-yl-hydroperoxid (64.1 μL, 0.47 mmol) is added slowly.The mixture is stirred at 90° C. for 1 hour.

Yield: 8 mg (25% of theory)

Mass spectrometry (ESI⁺): m/z=338 [M+H]⁺

HPLC (Method 4): Retention time=0.75 min.

Example 812-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-methylpyrimidine-5-carbonitrile

Analogously to example 80 obtained as a by-product by starting from2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-5-carbonitrile(example 77) and sodium trifluoromethanesulfinate. The mixture ispurified by RP-HPLC (modifier: trifluoroacetic acid)

Yield: 15% of theory

Mass spectrometry (ESI⁺): m/z=282 [M+H]⁺

HPLC (Method 4): Retention time=0.69 min.

Example 82 2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-4-(1,1-difluoroethyl)pyrimidine-5-carbonitrile

Analogously to example 80 obtained by starting from2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-5-carbonitrile(example 77) and sodium 1,1-difluoroethane-1-sulfinate.

Yield: 36% of theory

Mass spectrometry (ESI⁺): m/z=332 [M+H]⁺

HPLC (Method 4): Retention time=0.83 min.

Example 836-[5-bromo-4-(trifluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

Analogously to example 80 obtained by starting from6-(5-bromo-pyrimidin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 31) and zinc trifluoromethanesulfinate. The mixture is purifiedby RP-HPLC (modifier: ammonium hydroxide)

Yield: 45% of theory

Mass spectrometry (ESI⁺): m/z=389, 391 [M+H]⁺

HPLC (Method 1): Retention time=0.96 min.

Example 846-[5-bromo-4-(difluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

Analogously to example 80 obtained by starting from6-(5-bromo-pyrimidin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 31) and zinc difluoromethanesulfinate. The mixture is purifiedby RP-HPLC (modifier: ammonium hydroxide)

Yield: 29% of theory

Mass spectrometry (ESI⁺): m/z=371, 373 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 856-(6-Methanesulfinyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

5-Methyl-6-(6-methylsulfanyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 16) (200 mg, 0.70 mmol) is dissolved in 10 mL dichloromethane.3-chloroperoxybenzoic acid (274.5 mg, 1.60 mmol) is added and themixture is stirred at room temperature for 30 minutes. The reactionmixture is concentrated under reduced pressure and the residue ispurified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 75 mg (35% of theory)

Mass spectrometry (ESI⁺): m/z=304 [M+H]⁺

HPLC (Method 3): Retention time=0.65 min.

Example 866-(6-Methanesulfonyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 85 obtained by starting from5-Methyl-6-(6-methylsulfanyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 16) and 3-chloroperoxybenzoic acid. The reaction mixture isconcentrated and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 33% of theory

Mass spectrometry (ESI⁺): m/z=320 [M+H]⁺

HPLC (Method 3): Retention time=0.68 min.

Example 876-(5-Methanesulfinyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 85 obtained by starting from5-methyl-6-(5-methylsulfanyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 44) and 3-chloroperoxybenzoic acid. The mixture is concentratedand purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 54% of theory

Mass spectrometry (ESI⁺): m/z=304 [M+H]⁺

HPLC (Method 3): Retention time=0.60 min.

Example 886-(5-Methanesulfonyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 85 obtained by starting from5-methyl-6-(5-methylsulfanyl-pyridin-2-ylmethyl)-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 44) and 3-chloroperoxybenzoic acid. The mixture is concentratedand purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 38% of theory

Mass spectrometry (ESI⁺): m/z=320 [M+H]⁺

HPLC (Method 3): Retention time=0.65 min.

Example 896-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-trifluoromethyl-pyridine-2-carboxylicAcid Amide

6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-trifluoromethyl-pyridine-2-carbonitrile(example 48) (50.0 mg, 0.15 mmol) and sodium hydroxide (2.0 mL, 34.7mmol) are dissolved in 2.0 mL ethanol and the reaction mixture isstirred at 50° C. for 2 hours. The reaction mixture is cooled to roomtemperature, acidified with 4 M hydrochloric acid (74.8 μL, 0.30 mmol)and purified by RP-HPLC (modifier: trifluoroacetic acid).

Yield: 14 mg (26% of theory)

Mass spectrometry (ESI⁺): m/z=353 [M+H]⁺

HPLC (Method 3): Retention time=0.72 min.

Example 906-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-difluoromethoxy-pyridine-2-carboxylicAcid Amide

Analogously to example 89 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-difluoromethoxy-pyridine-2-carbonitrile(example 70). The mixture is purified without addition hydrochloric acidby RP-HPLC (modifier: ammonium hydroxide).

Yield: 50% of theory

Mass spectrometry (ESI⁺): m/z=351 [M+H]⁺

HPLC (Method 1): Retention time=0.72 min.

Example 916-[5-Bromo-6-(3,3,3-trifluoro-propoxy)-pyridin-2-ylmethyl]-5-methyl[-1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

6-(5-Bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) (45.0 mg, 0.13 mmol), 3,3,3-trifluoro-propan-1-ol (151.8mg, 1.33 mmol)) and cesium carbonate (108.4 mg, 0.33 mmol) are dissolvedin 1.0 mL of tetrahydrofuran. and stirred at 120° C. for 15 minutes. Thereaction mixture is concentrated under reduced pressure and the residueis purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 36 mg (62% of theory)

HPLC (Method 5): Retention time=0.89 min.; m/z=431, 433 [M+H]⁺

Example 926-[5-Bromo-6-(2,2-difluoro-ethoxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 2,2-difluoro-ethanol.

Yield: 103% of theory

HPLC (Method 5): Retention time=0.82 min.; m/z=399, 401 [M+H]⁺

Example 93 6-[5-Bromo-6-(2,2-difluoro-cyclopropylmethoxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and (2,2-difluorocyclopropyl)methanol.

Yield: 68% of theory

HPLC (Method 5): Retention time=0.88 min.; m/z=425, 427 [M+H]⁺

Example 941-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-bromo-pyridin-2-yloxy]-2-methyl-propan-2-ol

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 2-methyl-propane-1,2-diol.

Yield: 47% of theory

HPLC (Method 5): Retention time=0.76 min.; m/z=409, 411 [M+H]⁺

Example 956-[5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 3-methyl-3-oxetanemethanol.

Yield: 63% of theory

HPLC (Method 5): Retention time=0.81 min.; m/z=420, 422 [M+H]⁺

Example 966-[5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 2,2,2-trifluoro-ethanol.

Yield: 74% of theory

HPLC (Method 5): Retention time=0.87 min.; m/z=417, 419 [M+H]⁺

Example 976-(5-Bromo-6-methoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and methanol, use N-methyl-2-pyrrolidone instead oftetrahydrofuran as solvent.

Yield: 70% of theory

HPLC (Method 5): Retention time=0.83 min.; m/z=350, 352 [M+H]⁺

Example 986-[5-Bromo-6-(oxetan-3-yloxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and oxetan-3-ol.

Yield: 15% of theory

HPLC (Method 10): Retention time=0.82 min.; m/z=392, 394 [M+H]⁺

Example 996-[5-Bromo-6-(2,2-difluoro-propoxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 2,2-difluoro-propan-1-ol.

Yield: 87% of theory

HPLC (Method 10): Retention time=0.97 min.; 414, 416 [M+H]⁺

Example 1006-[5-Bromo-6-(2-fluoro-ethoxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 2-fluoro-ethanol.

Yield: 62% of theory

HPLC (Method 1): Retention time=0.95 min.; m/z=382, 384 [M+H]⁺

Example 101 6-[5-Bromo-6-(3-fluoro-propoxy)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 91 obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) and 3-fluoro-propan-1-ol.

Yield: 36% of theory

HPLC (Method 1): Retention time=1.00 min.; m/z=396, 398 [M+H]⁺

Example 1026-(5-Bromo-6-methylsulfanyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

6-(5-Bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(40.00 mg; 0,113 mmol) (example 19) and sodium methanethiolate (11,860mg; 0.170 mmol) dissolved in 2 ml tetrahydrofuran/dimethylformamide=1/1. Stirred at 120° C. for 18 hours. The mixture is purifiedby RP-HPLC (modifier: ammonium hydroxide).

Yield: 9 mg (21% of theory)

HPLC (Method 4): Retention time=0.96 min.; m/z=366, 368 [M+H]⁺

Example 1036-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2,2-difluoro-propoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 2,2-difluoro-propan-1-ol.

Yield: 43% of theory

Mass spectrometry (ESI⁻): m/z=361 [M+H]⁺

HPLC (Method 1): Retention time=0.90 min.

Example 1046-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(oxetan-3-yloxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and oxetan-3-ol.

Yield: 55% of theory

Mass spectrometry (ESI⁻): m/z=339 [M+H]⁺

HPLC (Method 1): Retention time=0.79 min.

Example 1056-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2-hydroxy-2-methyl-propoxy)nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 2-methylpropane-1,2-diol.

Yield: 49% of theory

Mass spectrometry (ESI⁻): m/z=355 [M+H]⁺

HPLC (Method 1): Retention time=0.84 min.

Example 1066-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2-fluoro-ethoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 2-fluoro-ethanol.

Yield: 50% of theory

Mass spectrometry (ESI⁻): m/z=329 [M+H]⁺

HPLC (Method 1): Retention time=0.84 min.

Example 1076-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2,2,2-trifluoro-ethoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 2,2,2-trifluoro-ethanol.

Yield: 46% of theory

Mass spectrometry (ESI⁻): m/z=365 [M+H]⁺

HPLC (Method 1): Retention time=0.91 min.

Example 1086-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3-fluoro-propoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 3-fluoro-propan-1-ol.

Yield: 28% of theory

Mass spectrometry (ESI⁻): m/z=343 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 1096-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2,2-difluoro-ethoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 2,2-difluoro-ethanol.

Yield: 49% of theory

Mass spectrometry (ESI⁻): m/z=347 [M+H]⁺

HPLC (Method 1): Retention time=0.87 min.

Example 1106-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3,3,3-trifluoro-propoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 3,3,3-trifluoro-propan-1-ol.

Yield: 37% of theory

Mass spectrometry (ESI⁻): m/z=379 [M+H]⁺

HPLC (Method 1): Retention time=0.94 min.

Example 1116-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3-methyl-oxetan-3-ylmethoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 3-methyl-3-oxetane-methanol.

Yield: 51% of theory

Mass spectrometry (ESI⁻): m/z=367 [M+H]⁺

HPLC (Method 1): Retention time=0.85 min.

Example 1126-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2,2-difluoro-cyclopropylmethoxy)-nicotinonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and (2,2-difluorocyclopropyl)-methanol.

Yield: 54% of theory

Mass spectrometry (ES⁻): m/z=373 [M+H]⁻

HPLC (Method 1): Retention time=0.91 min.

Example 1136-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) and 3,3,3-trifluoro-propan-1-ol.

Yield: 60% of theory

Mass spectrometry (ESI⁻): m/z=283 [M+H]⁺

HPLC (Method 1): Retention time=0.52 min.

Example 1146-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 2,2,2-trifluoro-ethanol. The mixture is purified byRP-HPLC (modifier: trifluoroacetic acid).

Yield: 58% of theory

Mass spectrometry (ESI⁻): m/z=365 [M+H]⁺

HPLC (Method 5): Retention time=0.90 min.

Example 1156-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(2-fluoro-ethoxy)-pyridine-2-carbonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 2-fluoro-ethanol. The mixture is purified by RP-HPLC(modifier: trifluoroacetic acid).

Yield: 50% of theory

Mass spectrometry (ESI⁻): m/z=329 [M+H]⁺

HPLC (Method 5): Retention time=0.78 min.

Example 1166-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(2,2-difluoro-ethoxy)-pyridine-2-carbonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 2,2-difluoro-ethanol.

Yield: 21% of theory

Mass spectrometry (ESI⁻): m/z=347 [M+H]⁺

HPLC (Method 12): Retention time=0.71 min.

Example 1176-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(2-methyl-2H-pyrazol-3-yloxy)-pyridine-2-carbonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 2-methyl-2H-pyrazol-3-ol.

Yield: 51% of theory

Mass spectrometry (ESI⁻): m/z=363 [M+H]⁺

HPLC (Method 1): Retention time=0.86 min.

Example 1186-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-phenoxy-pyridine-2-carbonitrile

Analogously to example 91 obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and phenol.

Yield: 33% of theory

Mass spectrometry (ESI⁻): m/z=359 [M+H]⁺

HPLC (Method 1): Retention time=0.99 min.

Example 1196-(6-Amino-5-difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

6-(6-Bromo-5-difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 15) (50.00 mg, 0.129 mmol), 2,4-dimethoxy-benzylamine (86.601mg, 0.518 mmol) and N,N-diisopropylethylamine (67.190 μL, 0.388 mmol) in2 mL dimethylsulfoxide are stirred at 120° C. for 18 hours. The mixtureis purified by RP-HPLC (modifier: ammonium hydroxide). The residue isdissolved in 2 mL dichloromethane, acidified with 0.50 mLtrifluoroacetic acid, stirred at room temperature for 3 h andconcentrated under reduced pressure.

Yield: 24 mg (35% of theory)

Mass spectrometry (ESI⁺): m/z=323 [M+H]⁺

HPLC (Method 1): Retention time=0.60 min.

Example 1206-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-difluoromethoxy-1H-pyridin-2-one

Analogously to example 91 obtained by starting from6-(6-bromo-5-difluoromethoxy-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 15) and 3,3,3-trifluoro-propan-1-ol.

Yield: 38% of theory

Mass spectrometry (ESI⁻): m/z=324 [M+H]⁺

HPLC (Method 1): Retention time=0.63 min.

Example 1216-{5-Bromo-6-[(3-methyl-oxetan-3-ylmethyl)-amino]-pyridin-2-ylmethyl}-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

6-(5-Bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) (30.00 mg, 0.085 mmol),C-(3-methyl-oxetan-3-yl)-methylamine (128.36 mg, 0.001 mol) andpotassium fluoride (24.578 mg, 0.423 mmol) are dissolved in 3 mLN-methyl-2-pyrrolidinon and stirred for 3 hours at 150° C. The mixtureis purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 53% of theory

Mass spectrometry (ESI⁺): m/z=419, 421 [M+H]⁺

HPLC (Method 1): Retention time=0.95 min.

Example 1221-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-bromo-pyridin-2-yl]-3-methyl-azetidin-3-ol

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and 3-methyl-3-azetidinol using triethylamine andacetonitrile instead of potassium fluoride and N-methyl-2-pyrrolidinon.

Yield: 39% of theory

Mass spectrometry (ESI⁺): m/z=405, 407 [M+H]⁺

HPLC (Method 1): Retention time=0.92 min.

Example 1236-(5-Bromo-6-morpholin-4-yl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and morpholine.

Yield: 78% of theory

Mass spectrometry (ESI⁺): m/z=405, 407 [M+H]⁺

HPLC (Method 1): Retention time=0.96 min.

Example 1243-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-bromo-pyridin-2-ylamino]-2,2-dimethyl-propionamide

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and 3-amino-2,2-dimethyl-propionamide.

Yield: 32% of theory

Mass spectrometry (ESI⁺): m/z=434, 436 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

Example 1256-(5-Bromo-6-cyclopropylamino-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and cyclopropylamine.

Yield: 30% of theory

Mass spectrometry (ESI⁺): m/z=375, 377 [M+H]⁺

HPLC (Method 1): Retention time=1.03 min.

Example 1266-{5-Bromo-6-[(3-methyl-tetrahydro-furan-3-ylmethyl)-amino]-pyridin-2-ylmethyl}-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and C-(3-methyl-tetrahydro-furan-3-yl)methylamine.

Yield: 71% of theory

Mass spectrometry (ESI⁺): m/z=433, 435 [M+H]⁺

HPLC (Method 4): Retention time=0.95 min.

Example 1273-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-bromo-pyridin-2-ylamino]-2,2-di methyl-propionitrile

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and 3-amino-2,2-dimethyl-propionitrile.

Yield: 12% of theory

Mass spectrometry (ESI⁺): m/z=416, 418 [M+H]⁺

HPLC (Method 4): Retention time=0.90 min.

Example 1286-[5-Bromo-6-(3,3-difluoro-cyclobutylamino)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19), 3,3-difluoro-cyclobutylamine and additional triethylamine.Stirred for 5 hours at 150° C., quenched with methanol, filtered andpurified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 10% of theory

Mass spectrometry (ESI⁺): m/z=425, 427 [M+H]⁺

HPLC (Method 1): Retention time=0.98 min.

Example 1296-[5-Bromo-6-(3,3-difluoro-azetidin-1-yl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19), 3,3-difluoroazetidine hydrochloride and additionaltriethylamine. Stirred for 5 hours at 150° C., quenched with methanol,filtered and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 26% of theory

HPLC (Method 5): Retention time=0.88 min., m/z=410, 412 [M+H]⁺

Example 1306-[5-Bromo-6-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and 2-oxa-6-aza-spiro[3,3]heptane oxalic acid salt usingdiisopropylethylamine instead of potassium fluoride. The reactionmixture was stirred for 2 hours at 120° C., cooled to room temperature,diluted with methanol and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 47% of theory

HPLC (Method 1): Retention time=0.89 min., m/z=416, 418 [M+H]⁺

Example 1311-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-bromo-pyridin-2-yl]-[1,4]diazepan-5-one

Obtained analogously to example 121 by starting6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and [1,4]diazepam-5-one using diisopropylethylamine insteadof potassium fluoride.

Yield: 46% of theory

HPLC (Method 1): Retention time=0.83 min., m/z=433, 435 [M+H]⁺

Example 1326-[5-Bromo-6-(3,3-difluoro-pyrrolidin-1-yl)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19), 3,3-Difluoro-pyrrolidine hydrochloric salt and additionaldiisopropylethylamine.

Yield: 19% of theory

HPLC (Method 1): Retention time=1.04 min., m/z=424, 426 [M+H]⁺

Example 1336-[5-Bromo-6-(3,3-difluoro-propylamino)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19) and 3,3-difluoro-propylamine hydrochloride salt. Stirredfor 18 hours at 150° C., quenched with methanol, filtered and purifiedby RP-HPLC (modifier: ammonium hydroxide).

Yield: 17% of theory

HPLC (Method 1): Retention time=0.98 min., m/z=412, 414 [M+H]⁺

Example 1346-[5-Bromo-6-(3,3,3-trifluoro-propylamino)-pyridin-2-ylmethyl]-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Obtained analogously to example 121 by starting from6-(5-bromo-6-chloro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 19), 3,3,3-trifluoro-propylamine hydrochloride salt andadditional diisopropylethylamine. Stirred 1 hour at 150° C., quenchedwith methanol, filtered and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 11% of theory

HPLC (Method 1): Retention time=0.93 min., m/z=430, 432 [M+H]⁺

Example 1356-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-[(3-methyl-oxetan-3-ylmethyl)-amino]-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and C-(3-methyl-oxetan-3-yl)-methylamine.

Yield: 38% of theory

Mass spectrometry (ESI⁺): m/z=366 [M+H]⁺

HPLC (Method 1): Retention time=0.83 min.

Example 1366-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-morpholin-4-yl-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and morpholine.

Yield: 41% of theory

Mass spectrometry (ESI⁺): m/z=352 [M+H]⁺

HPLC (Method 10): Retention time=0.68 min.

Example 1376-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-nicotinonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and 2-oxa-6-aza-spiro[3,3]heptane oxalic acid salt usingdiisopropylethylamine instead of potassium fluoride.

Yield: 58% of theory

Mass spectrometry (ESI⁺): m/z=364 [M+H]⁺

HPLC (Method 1): Retention time=0.82 min.

Example 1386-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3-hydroxy-3-methyl-azetidin-1-yl)-nicotinonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and 3-methyl-3-azetidinol using triethylamin instead ofpotassium fluoride.

Yield: 72% of theory

Mass spectrometry (ESI⁺): m/z=352 [M+H]⁺

HPLC (Method 1): Retention time=0.82 min.

Example 1396-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-cyclopropylamino-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and cyclopropylamine.

Yield: 27% of theory

Mass spectrometry (ESI⁺): m/z=322 [M+H]⁺

HPLC (Method 1): Retention time=0.83 min.

Example 1406-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3,3-difluoro-cyclobutylamino)-nicotinonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and 3,3-difluoro-cyclobutylamine usingdiisopropylethylamine instead of potassium fluoride.

Yield: 67% of theory

Mass spectrometry (ESI⁺): m/z=372 [M+H]⁺

HPLC (Method 1): Retention time=0.93 min.

Example 1416-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(5-oxo-[1,4]diazepan-1-yl)-nicotinonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and [1,4]diazepam-5-one using diisopropylethylamine insteadof potassium fluoride.

Yield: 68% of theory

Mass spectrometry (ESI⁺): m/z=379 [M+H]⁺

HPLC (Method 1): Retention time=0.74 min.

Example 142 6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3,3-difluoro-azetidin-1-yl)-nicotinonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and 3,3-Difluoro-azetidine hydrochloric salt usingdiisopropylethylamine instead of potassium fluoride.

Yield: 63% of theory

Mass spectrometry (ESI⁺): m/z=358 [M+H]⁺

HPLC (Method 1): Retention time=0.91 min.

Example 1436-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3,3-difluoro-pyrrolidin-1-yl)-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24), 3,3-Difluoro-pyrrolidine hydrochloride and additionaldiisopropylethylamine.

Yield: 69% of theory

Mass spectrometry (ESI⁺): m/z=372 [M+H]⁺

HPLC (Method 1): Retention time=0.93 min.

Example 1446-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3,3-difluoro-propylamino)-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24), 3,3-difluoropropylamine hydrochloride salt anddiisopropylethylamine. Stirred for 30 minutes at 150° C. quenched withmethanol, filtered and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 85% of theory

Mass spectrometry (ESI⁺): m/z=360 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

Example 1456-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3,3,3-trifluoro-propylamino)-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24), 3,3,3-trifluoro-propylamine hydrochloride salt andadditional diisopropylethylamine.

Yield: 77% of theory

Mass spectrometry (ESI⁺): m/z=378 [M+H]⁺

HPLC (Method 1): Retention time=0.91 min.

Example 1466-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(2-cyano-2,2-dimethyl-ethylamino)-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and 3-amino-2,2-dimethyl-propionitrile.

Yield: 37% of theory

Mass spectrometry (ESI⁺): m/z=363 [M+H]⁺

HPLC (Method 1): Retention time=0.86 min.

Example 1476-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-[(3-methyl-tetrahydro-furan-3-ylmethyl)-amino]-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-yl-methyl)-2-chloro-nicotinonitrile(example 24) and C-(3-methyl-tetrahydro-furan-3-yl)-methylamine.

Yield: 60% of theory

Mass spectrometry (ESI⁺): m/z=380 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

Example 1483-[6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-cyano-pyridin-2-ylamino]-2,2-dimethyl-propionamide

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24) and 3-Amino-2,2-dimethyl-propionamide.

Yield: 68% of theory

Mass spectrometry (ESI⁺): m/z=381 [M+H]⁺

HPLC (Method 1): Retention time=0.79 min.

Example 1496-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-(3-fluoro-propylamino)-nicotinonitrile

Obtained analogously to example 121 by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-chloro-nicotinonitrile(example 24), 3-Fluoro-propylamine hydrochloride salt and additionaldiisopropylethylamine. Stirred for 30 minutes at 150° C., quenched withmethanol, filtered and purified by RP-HPLC (modifier: ammoniumhydroxide).

Yield: 75% of theory

Mass spectrometry (ESI⁺): m/z=342 [M+H]⁺

HPLC (Method 1): Retention time=0.89 min.

Example 1506-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 3,3-difluoro-pyrrolidine hydrochloric salt usingdiisopropylethylamine instead of potassium fluoride.

Yield: 39% of theory

Mass spectrometry (ESI⁺): m/z=372 [M+H]⁺

HPLC (Method 5): Retention time=0.74 min.

Example 1516-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 3,3-difluoro-azetidine hydrochloric salt usingdiisopropylethylamine instead of potassium fluoride.

Yield: 38% of theory

Mass spectrometry (ESI⁺): m/z=358 [M+H]⁺

HPLC (Method 5): Retention time=0.72 min.

Example 1526-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-morpholin-4-yl-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and morpholine using diisopropylethylamine instead ofpotassium fluoride.

Yield: 35% of theory

Mass spectrometry (ESI⁺): m/z=352 [M+H]⁺

HPLC (Method 5): Retention time=0.64 min.

Example 1536-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(2-fluoro-ethylamino)-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 2-fluoro-ethylamine hydrochloric salt usingdiisopropylethylamine instead of potassium fluoride.

Yield: 31% of theory

Mass spectrometry (ESI⁺): m/z=328 [M+H]⁺

HPLC (Method 1): Retention time=0.83 min.

Example 1546-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(2,2-difluoro-ethylamino)-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 2,2-difluoro-ethylamine using diisopropylethylamineinstead of potassium fluoride.

Yield: 17% of theory

Mass spectrometry (ESI⁺): m/z=346 [M+H]⁺

HPLC (Method 1): Retention time=0.86 min.

Example 1556-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(4-fluoro-pyrazol-1-yl)-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 4-fluoro-1H-pyrazole using diisopropylethylamineinstead of potassium fluoride.

Yield: 28% of theory

Mass spectrometry (ESI⁺): m/z=351 [M+H]⁺

HPLC (Method 1): Retention time=0.87 min.

Example 1566-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-(3-trifluoromethyl-pyrazol-1-yl)-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 3-trifluoromethyl-1H-pyrazole usingdiisopropylethylamine instead of potassium fluoride.

Yield: 18% of theory

Mass spectrometry (ESI⁺): m/z=401 [M+H]⁺

HPLC (Method 13): Retention time=0.65 min.

Example 1576-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-pyrazol-1-yl-pyridine-2-carbonitrile

Obtained analogously to example 121 by starting6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-fluoro-pyridine-2-carbonitrile(example 25) and 1H-pyrazole using diisopropylethylamine instead ofpotassium fluoride.

Yield: 31% of theory

Mass spectrometry (ESI⁺): m/z=333 [M+H]⁺

HPLC (Method 1): Retention time=0.83 min.

Example 1586-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2,3-dicarbonitrile

6-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72) (150.00 mg, 0.528 mmol) and potassium cyanide (51.543 mg,0.792 mmol) are dissolved in 4 mL of dimethyl sulfoxide and stirred atroom temperature for 1 hour. The mixture is extracted with ethyl acetateand washed with a half saturated aqueous solution of sodium bicarbonate.The organic phase is concentrated under reduced pressure and purified bysilica gel chromatography (eluent: cyclohexane/ethyl acetate100/0→45/65). The product is crystallized from ethylacetate/cyclohexane=1/1 and collected by filteration.

Yield: 72% of theory

Mass spectrometry (ESI⁺): m/z=292 [M+H]⁺

HPLC (Method 1): Retention time=0.80 min.

Example 1596-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-methanesulfonyl-pyridin-2-ol

6-(5-Bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) (50.00 mg, 0.148 mmol) and sodium methanesulfinate (15.096mg, 0.148 mmol) are dissolved in 0.909 mL of dimethyl sulfoxide andstirred for 1 hour at 100° C. in a microwave. The mixture is purified byRP-HPLC (modifier: ammonium hydroxide).

Yield: 8 mg (16% of theory)

Mass spectrometry (ESI⁺): m/z=336 [M+H]⁺

HPLC (Method 1): Retention time=0.55 min.

Example 1606-(5,6-Bis-methanesulfonyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 159, obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22).

Yield: 13% of theory

Mass spectrometry (ESI⁺): m/z=398 [M+H]⁺

HPLC (Method 1): Retention time=0.63 min.

Example 1616-(5-Bromo-6-methanesulfonyl-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine

Analogously to example 159, obtained by starting from6-(5-bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22).

Yield: 8% of theory

Mass spectrometry (ESI⁺): m/z=398, 399, 401 [M+H]⁺

HPLC (Method 1): Retention time=0.71 min.

Example 1626-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-methanesulfonyl-nicotinonitrile

Analogously to example 159, obtained by starting from6-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-2-fluoro-nicotinonitrile(example 72).

Yield: 24 mg (39% of theory)

Mass spectrometry (ESI⁺): m/z=345 [M+H]⁺

HPLC (Method 1): Retention time=0.70 min.

Example 1636-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-3-bromo-1H-pyridin-2-one

6-(5-Bromo-6-fluoro-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 22) (50.00 mg, 0.148 mmol) and potassium hydroxide (5 M aqueoussolution) (0.10 ml, 0.35 mmol) are dissolved in 1.0 mL of dimethylsulfoxide and stirred for 5 minutes at 120° C. The mixture is purifiedby RP-HPLC (modifier: ammonium hydroxide).

Yield: 36 mg (72% of theory)

Mass spectrometry (ESI⁺): m/z=336, 338 [M+H]⁺

HPLC (Method 1): Retention time=0.61 min.

Example 1646-(7-Amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-pyridine-2-carbonitrile

164.1N′-(6-Iodo-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-yl)-N,N-dimethyl-formamidine

6-Iodo-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine G (3.50 g,12.7 mmol) is dissolved in 35 mL N,N-dimethylformamide andN,N-dimethylformamide dimethyl acetale (2.04 ml, 15.2 mmol) is added atroom temperature. The mixture is stirred 1 hour, diluted with diethylether and the product is collected by filteration.

Yield: 2.57 g (61% of theory)

Mass spectrometry (ESI⁺): m/z=332 [M+H]⁺

HPLC (Method 12): Retention time=0.95 min.

164.2N′-[6-(6-Cyano-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-yl]-N,N-dimethyl-formamidine

N′-(6-Iodo-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-yl)-N,N-dimethyl-formamidine164.1 (100 mg, 0.302 mmol) and lithium acetylacetonate (3 mg, 0.030mmol) are dissolved in 0.50 mL N-methyl-2-pyrrolidone. The reactionmixture is cooled to 0° C., diisopropylzinc solution (1 M solution intoluene, 0.166 ml, 0.166 mmol) is added and the reaction mixture isstirred at room temperature for 18 hours.[1,1′-bis(di-tert-butylphosphino)-ferrocene]palladium (II) dichloride(19 mg, 0.030 mmol) and 6-Bromomethyl-pyridine-2-carbonitrile (purchasedfrom ABCR GmbH & Co. KG) (89 mg, 0.453 mmol) are added and the reactionmixture is stirred at 80° C. for 2 hours. The reaction mixture dilutedwith ethyl acetate, filtered over alox, concentrated under reducedpressure and purified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 21 mg (21% of theory)

Mass spectrometry (ESI⁺): m/z=322 [M+H]⁺

HPLC (Method 1): Retention time=0.93 min.

Final Step (Example 164)

ToN′-[6-(6-Cyano-pyridin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo-[3,4-b]pyridin-7-yl]-N,N-dimethyl-formamidine164.2 (20.00 mg, 0.062 mmol) in 10 mL of methanol is added 1.0 mL conc.hydrochloric acid and the reaction mixture is stirred for 2 hours at 60°C. The mixture is poured slowly into saturated aqueous solution ofsodium bicarbonate and extracted with ethyl acetate. The organic phasesare dried, concentrated under reduced pressure and the residue ispurified by RP-HPLC (modifier: ammonium hydroxide).

Yield: 11 mg (70% of theory)

Mass spectrometry (ESI⁺): m/z=267 [M+H]⁺

HPLC (Method 1): Retention time=0.75 min.

Example 1652-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)-6-(difluoromethyl)pyrimidine-4-carbonitrile

2-(7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-6-ylmethyl)pyrimidine-4-carbonitrile(example 51) (160 mg, 0.60 mmol) is dissolved in 6.0 mL dichloromethaneand 2.0 mL water and zinc difluoromethanesulfinate (0.48 g, 1.62 mmol)is added. Trifluoroacetic acid (0.05 mL, 0.62 mmol) and2-methyl-prop-2-yl-hydroperoxide (0.39 g, 2.99 mmol) are added and themixture is stirred at room temperature for 18 hours. The solvent isconcentrated under reduced pressure and the residue is purified byRP-HPLC (modifier: ammonium hydroxide)

Yield: 6.0 mg (3% of theory)

Mass spectrometry (ESI⁺): m/z=318 [M+H]⁺

HPLC (Method 1): Retention time=0.82 min.

Example 1666-[5-chloro-4-(difluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

and

Example 1676-[5-chloro-4,6-bis(difluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

Analogously to example 80 obtained by starting from6-(5-chloro-pyrimidin-2-ylmethyl)-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-ylamine(example 30) and zinc difluoromethanesulfinate. The mixture is purifiedby RP-HPLC (modifier: ammonium hydroxide)

6-[5-chloro-4-(difluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

Yield: 28% of theory

Mass spectrometry (ESI⁻): m/z=327 [M+H]⁺

HPLC (Method 1): Retention time=0.88 min.

6-[5-chloro-4,6-bis(difluoromethyl)pyrimidin-2-yl]methyl-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridin-7-amine

Yield: 11% of theory

Mass spectrometry (ESI⁺): m/z=377 [M+H]⁺

HPLC (Method 1): Retention time=0.94 min.

The invention claimed is:
 1. A method for treating obesity, type 2diabetes mellitus, and/or insulin resistance, the method comprisingadministering to a patient in need thereof a pharmaceutically effectiveamount of a compound of formula (I)

wherein X is CH or N; R¹ is selected from the group consisting ofCH₃—CH₂OH CH₃, —CH₂OH and Cl; R² is independently of each other selectedfrom the group consisting of H, F, Cl, Br, I, CN, C₁₋₆-alkyl,C₃₋₇-cycloalkyl, OH, —O—(C₁₋₆-alkyl), —O—(C₃₋₇-cycloalkyl),—O—(C₁₋₃-alkyl)-(C₃₋₇-cyclo alkyl) —O—(C₁₋₃-alkyl)-(C₃₋₇-cycloalkyl),—O-heterocyclyl, —O—(C₁₋₃-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl,—S—(C₁₋₃-alkyl), —SO—(C₁₋₃-alkyl), —SO₂₁₋₃-alkyl) —SO₂-(C₁₋₃alkyl),—NH₂, —NH—(C₁₋₆-alkyl), —NH—(C₃₋₆-cycloalkyl),—NH—(C₁₋₃-alkyl)-heterocyclyl,—NH—(C₁₋₆-alkyl-C(═O)—NH₂—C(═O)—NH₂—C(═O)—NH—(C₁₋₃-alkyl)—NH—(C₁₋₆-alkyl)-C(═O)—NH₂, —C(═O)—NH₂, —C(═O)—NH—(C₁₋₃-alkyl),—C(═O)—N(C₁₋₃-alkyl)₂, —C(═O)OH, —C(═O)—O—(C₁₋₄-alkyl),—C(═O)—(C₁₋₄-alkyl), alkyl) —C₁₋₃-alkyl-C(═O)—O—(C₁₋₄-alkyl),heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,wherein each alkyl or cycloalkyl group is optionally independentlysubstituted with one or more substituents selected from the groupconsisting of F, CN and OH, and wherein each heterocyclyl group isselected from the group consisting of a mono- or spirocyclic4-7-membered cycloalkyl group, in which 1, 2 or 3 CH₂-groups areindependently of each other replaced by O, S, NH or C═O, and whereineach heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from the groupconsisting of F, OH and C₁₋₃-alkyl, wherein each aryl group is selectedfrom the group consisting of phenyl and naphthyl, and wherein eachheteroaryl group is selected from the group consisting of a 5-memberedaromatic cycle containing 1 or 2 heteroatoms independently selected fromthe group consisting of N, O and S or from a 6-membered aromatic cyclecontaining 1 or 2 N, and wherein each aryl or heteroaryl group isoptionally substituted with 1 or 2 substituents independently selectedfrom the group consisting of F, CN and C₁₋₃-alkyl, which is optionallysubstituted with one or more F; or, if two groups R² are attached toadjacent C atoms of the pyridine or pyrimidine group, they may be linkedwith each other and together form a O—CH₂—O— —O—CH₂—O—, —O—CH₂—CH₂—O— or—O—CH₂—CH₂—CH₂—O— bridge, in which 1 or 2H 2 H atoms may be replacedwith F or C₁₋₃-alkyl; and n is 1, 2 or 3; wherein each of theabove-mentioned alkyl groups may be substituted with one or more F; or apharmaceutically acceptable salt thereof.
 2. A method for treating adisease or condition which is mediated by inhibiting the activity of theghrelin O-acyl transferase (GOAT), the method comprising administering acompound of formula (I)

wherein X is CH or N; R¹ is selected from the group consisting ofCH₃—CH₂OH CH₃, —CH₂OH and Cl; R² is independently of each other selectedfrom the group consisting of H, F, Cl, Br, I, CN, C₁₋₆-alkyl,C₃₋₇-cycloalkyl, OH, —O—(C₁₋₆-alkyl), —O—(C₃₋₇-cycloalkyl),—O—(C₁₋₃-alkyl)-(C₃₋₇-cycloalkyl), —O-heterocyclyl,—O—(C₁₋₃-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C₁₋₃-alkyl),—SO—(C₁₋₃-alkyl), —SO₂₁₋₃-alkyl) —SO₂—(C₁₋₃-alkyl), —NH₂,—NH—(C₁₋₆-alkyl), —NH—(C₃₋₆-cycloalkyl), —NH—(C₁₋₃-alkyl)-heterocyclyl,—NH—(C₁₋₆-alkyl)-C(═O )—NH₂, —C(═O)—NH₂, —C(═O)—NH—(C₁₋₃-alkyl),—C(═O)—N(C₁₋₃-alkyl)₂, —C(═O)OH, —C(═O)—O—(C₁₋₄-alkyl),—C(═O)—(C₁₋₄-alkyl), alkyl) —C₁₋₃-alkyl—C(═O)—O—(C₁₋₄-alkyl),heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,wherein each alkyl or cycloalkyl group is optionally independentlysubstituted with one or more substituents selected from the groupconsisting of F, CN and OH, and wherein each heterocyclyl group isselected from the group consisting of a mono- or spirocyclic4-7-membered cycloalkyl group, in which 1, 2 or 3 CH₂-groups areindependently of each other replaced by O, S, NH or C═O, and whereineach heterocyclyl group is optionally substituted with 1 or 2substituents independently of each other selected from the groupconsisting of F, OH and C₁₋₃-alkyl, wherein each aryl group is selectedfrom the group consisting of phenyl and naphthyl, and wherein eachheteroaryl group is selected from the group consisting of a 5-memberedaromatic cycle containing 1 or 2 heteroatoms independently selected fromthe group consisting of N, O and S or from a 6-membered aromatic cyclecontaining 1 or 2 N, and wherein each aryl or heteroaryl group isoptionally substituted with 1 or 2 substituents independently selectedfrom the group consisting of F, CN and C₁₋₃-alkyl, which is optionallysubstituted with one or more F; or, if two groups R² are attached toadjacent C atoms of the pyridine or pyrimidine group, they may be linkedwith each other and together form a O—CH_(2—O—) —O—CH₂—O—, —O—CH₂—CH₂—O—or —O—CH₂—CH₂—CH₂—O— bridge, in which 1 or 2H 2 H atoms may be replacedwith F or C₁₋₃-alkyl; and n is 1, 2 or 3; wherein each of theabove-mentioned alkyl groups may be substituted with one or more F; or apharmaceutically acceptable salt thereof, to a patient in need thereof.3. The method according to claim 1, wherein R¹ is —CH₃; and n is 1 or 2,or a pharmaceutically aceptable salt thereof.
 4. The method according toclaim 1, wherein R² is independently of each other selected from thegroup consisting of H, F, Cl, Br, CN, C₁₋₆-alkyl, C₃₋₇-cycloalkyl, OH,—O—(C₁₋₆-alkyl), —O—(C₁₋₃-alkyl)-(C₃₋₇-cycloalkyl), —O— heterocyclyl—O-heterocyclyl, —O—(C₁₋₃-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl,—S—(C₁₋₃-alkyl), —SO₂—(C₁₋₃-alkyl), —NH₂, —NH—(C₁₋₆-alkyl),—NH—(C₃₋₆-cycloalkyl), —NH—(C₁₋₃-alkyl)-heterocyclyl,—NH—(C₁₋₆-alkyl)-C(═O)—NH₂, —C(═O)—NH₂, —C(═O)—NH—(C₁₋₃-alkyl),—C(═O)—(C₁₋₄-alkyl), —C₁₋₃-alkyl-C(═O)—O—(C₁₋₄-alkyl), heterocyclyl,heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein eachalkyl or cycloalkyl group is optionally independently substituted withone or more substituents selected from the group consisting of F, CN andOH, and wherein each heterocyclyl group is selected from the groupconsisting of a mono- or spirocyclic 4-7-membered cycloalkyl group, inwhich 1, 2 or 3 CH₂-groups are independently of each other replaced byO, S, NH or C═O, and wherein each heterocyclyl group is optionallysubstituted with 1 or 2 substituents independently of each otherselected from the group consisting of F, OH and C₁₋₃-alkyl, wherein eacharyl group is selected from the group consisting of phenyl and naphthyl,and wherein each heteroaryl group is selected from the group consistingof a 5-membered aromatic cycle containing 1 or 2 heteroatomsindependently selected from the group consisting of N, O and S or from a6-membered aromatic cycle containing 1 or 2 N, and wherein each aryl orheteroaryl group is optionally substituted with 1 or 2 substituentsindependently selected from the group consisting of F and C₁₋₃-alkyl,which is optionally substituted with one or more F; or, if two groups R²are attached to adjacent C atoms of the pyridine or pyrimidine group,they may be linked with each other and together form a —O—CH₂—O—,—O—CH₂—CH₂—O— or —O —CH₂—CH₂—CH₂—O— —O—CH₂—CH₂—CH₂—O— bridge, or apharmaceutically acceptable salt thereof.
 5. The method according toclaim 4, wherein R² is independently of each other selected from thegroup consisting of F, Cl, Br, CN, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,—O—(C₁₋₄-alkyl), —O—CH₂-cyclopropyl, —O—CH₂-heterocyclyl, —O-phenyl,—O-heteroaryl, —S—CH₃, —NH₂, —NH—(C₁₋₄-alkyl), —NH—(C₃₋₅-cycloalkyl),—NH—(CH₂-heterocyclyl), —NH—(C₁₋₄-alkyl)-C(═O)—NH₂,—C(═O)—NH—(C₁₋₃-alkyl), —C(═O)—(C₁₋₄-alkyl), heterocyclyl, heteroaryland 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl orcycloalkyl group is optionally independently substituted with one tothree F atoms or with one CN or one OH, and wherein each heterocyclylgroup is selected from the group consisting of oxetanyl,tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl and1,4-diazepan-5-one, and wherein each heterocyclyl group is optionallysubstituted with 1 or 2 substituents independently of each otherselected from the group consisting of F, OH and CH₃, wherein eachheteroaryl group is selected from the group consisting of furanyl,isoxazolyl, thiazolyl and pyrazolyl, and wherein each heteroaryl groupis optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of F, CH₃ and CF₃, or apharmaceutically acceptable salt thereof.
 6. The method according toclaim 5, wherein R² is independently of each other selected from thegroup consisting of F, Cl, Br, CN, CH₃, C₃₋₅-cycloalkyl,—O—(C₁₋₄-alkyl), —O—CH₂-heterocyclyl, —O-phenyl, —S—CH₃, —NH₂,—NH—(C₁₋₄-alkyl), —NH—(C₃₋₅-cycloalkyl), —NH—(CH₂-heterocyclyl),—NH—(C₁₋₄-alkyl)-C(═O)—NH₂, heterocyclyl, heteroaryl and5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl, wherein each alkyl orcycloalkyl group is optionally independently substituted with one tothree F atoms or with one CN or one OH, and wherein each heterocyclylgroup is selected from the group consisting of oxetanyl, azetidinyl,pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and wherein eachheterocyclyl group is optionally substituted with 1 or 2 substituentsindependently selected from the group consisting of F, OH and CH₃, andwherein each heteroaryl group is selected from the group consisting offuranyl and thiazolyl, or a pharmaceutically acceptable salt thereof. 7.The method according to claim 6, wherein R² is independently selectedfrom the group consisting of: F, Cl, Br, —CN, —CF₃,

—O—CH₃, —O—CHF₂, —O—CH₂—CH₂—F, —O—CH₂—CHF₂, —O—CH₂—CF₃,—O—CH₂—CH₂—CH₂—F, —O—CH₂—CF₂—CH₃,

—S—CH₃, —NH₂, —NH—CH₂—CH₂—CH₂—F, —NH—CH₂—CH₂—CHF₂,

or a pharmaceutically acceptable salt thereof.
 8. The method accordingto claim 1, where X is CH, or a pharmaceutically acceptable saltthereof.
 9. The method according to claim 1, where X is N, or apharmaceutically acceptable salt thereof.
 10. The method according toclaim 1, where the compound of formula (I) is of formula I.2

wherein R¹ is CH₃; R^(2a) and R^(2b) are each independently selectedfrom the group consisting of: H, F, Cl, Br, CN, —CF₃,

—O—CH₃, —O—CHF₂, —O—CH₂—CH₂—F, —O—CH₂—CHF₂, —O—CH₂—CF₃,—O—CH₂—CH₂—CH₂—F, —O—CH₂—CF₂—CH₃,

—S—CH₃, —NH₂, —NH—CH₂—CH₂—CH₂—F, —NH—CH₂—CH₂—CHF₂,

wherein at least one R^(2a) and R^(2b) is not H; or a pharmaceuticallyacceptable salt thereof.
 11. The method according to claim 1, whereinthe compound of formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the obesity patient is suffering from Prader-Willi syndrome.13. The method according to claim 10, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 14. The method accordingto claim 10, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 16. The method accordingto claim 10, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 17. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 18. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 19. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 20. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 21. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 22. The method accordingto claim 10, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 23. The method accordingto claim 10, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 24. The method accordingto claim 10, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 25. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 26. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 27. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 28. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 29. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 30. The method accordingto claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 31. A method for treatingobesity, type 2 diabetes mellitus, and/or insulin resistance, the methodcomprising administering to a patient in need thereof a pharmaceuticallyeffective amount of a compound of formula


32. A method for treating obesity, type 2 diabetes mellitus, and/orinsulin resistance, the method comprising administering to a patient inneed thereof a pharmaceutically effective amount of a compound offormula


33. A method for treating obesity, type 2 diabetes mellitus, and/orinsulin resistance, the method comprising administering to a patient inneed thereof a pharmaceutically effective amount of a compound offormula


34. A method for treating obesity, type 2 diabetes mellitus, and/orinsulin resistance, the method comprising administering to a patient inneed thereof a pharmaceutically effective amount of a compound offormula


35. A method for treating obesity, type 2 diabetes mellitus, and/orinsulin resistance, the method comprising administering to a patient inneed thereof a pharmaceutically effective amount of a compound offormula


36. A method for treating obesity, type 2 diabetes mellitus, and/orinsulin resistance, the method comprising administering to a patient inneed thereof a pharmaceutically effective amount of a compound offormula


37. A method for treating obesity, type 2 diabetes mellitus, and/orinsulin resistance, the method comprising administering to a patient inneed thereof a pharmaceutically effective amount of a compound offormula